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Its Role in Disease and, Health
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Cover:

The emblem depicts the relationship be-
tween the body’s immunologic system and
disease. The maze symbolizes the varied and
complicated immune process and the “id”
each person’s unique immunologic mecha-
nism and responses.

 

 

 

The Doctor’s Office by Norman Rockwell. (Reprinted with permission from
The Saturday Evening Post, © 1958 The Curtis Publishing Company.)

IMMUNOLOGY

Its Role in Disease and Health

Summary Report
of the

Task Force on Immunology and Disease

DHEW Publication No. (NIH) 75—940

U.S. DEPARTMENT OF HEALTH, EDUCATION AND WELFARE
Public Health Service, National Institutes of Health
National Institute of Allergy and Infectious Diseases

Bethesda, Maryland 20014

Available from the
Superintendent of Documents
U.S. Government Printing Oflfice
Washington, D.C. 20402

Price $2.55
Stock Number 017—044—00021—4

Preface . .
Foreword

Chapter 1.

Chapter 2.

Chapter 3.

20 R

1131

lU531
1976

Contents 1pUBL

..........................................

THE OLD AND THE NEW IMMUNOLOGY ......

A. Early History of the Science of Self . . .
B. The New Immunology—Accomplish-
ments and Applications .............

THE IMMUNE RESPONSE ...................

. Antigens and Antibodies ............
Cellular Events in the Immune Re-
sponse ............................
Thymus-Derived (T) Lymphocytes
. Bone Marrow-Derived (B) Lympho-
cytes and Cellular Collaboration ......
Tolerance and Autoimmunity ........
Regulation of the Immune Response . .
Structure of Antibody Molecules ......
. Immunoglobulin Classes and Their
Function ..........................
I. Accessory Systems: Complement .....

mean 60‘w>

BIOLOGY OF THE IMMUNE SYSTEM: REPRODUC-
TION, NORMAL AND ABNORMAL DEVELOPMENT,
AND AGING .............................

A. Immunology and Reproduction .......
1. The maternal-fetal relationship . ..
2. Immunization resulting from
maternal-fetal exchanges .........
3. Anti-sperm, anti-seminal plasma,
and anti-placental antibodies ......
B. Immunology and Development .......
1. Development of the lymphoid system
and deficiencies of the immune
response .......................
2. Embryonic and carcino-embryonic
antigens .......................
3. Infectious disease ...............
a. Congenital (prenatal) in-
fection ......................

9261

ix
xi

10
10

13
13

14
15
15
17

18

23

25
25

26
29
30
30

33
35

35

b. Neonatal and childhood
infection .....................

C. Immunology and Aging .............

Chapter 4. INFECTIOUS DISEASES AND POST-INFECTION
COMPLICATIONS ..........................

A. Magnitude of the Problem ...........
B. Principles Of Vaccination ...........

1.

2.
3

Immunization against polio-
myelitis ........................
Smallpox vaccination ............
Successful vaccination against other
microbial diseases ...............
Infections for which vaccines might
shortly be developed .............
a. Influenza ....................
b. Pneumonia and meningitis .....
0. Future measures ..............
Infections requiring extensive re-
search for prevention and control . .
a. Venereal disease ..............
b. Viral hepatitis ...............
c. Common cold .................
The relationship between infection
and autoimmunity ...............
a. Rheumatic fever and glomerulo-
nephritis ....................
b. Tuberculosis .................
Unusual infectious diseases ......
a. Infections common to other coun-
tries ........................
b. Infections Of immunologically
suppressed persons ...........
0. Infection in primary immuno-
deficiency states ..............

C. Further Research Needed ...........
Chapter 5. DIAGNOSTIC IMMUNOLOGY AND
EPIDEMIOLOGY ...........................

A. Measurement of Serum Proteins in
Diagnosis and Management of
Diseases ..........................
Radioimmunoassays ................
Immunofiuorescent Techniques in the
Diagnosis Of Infectious Diseases ......

P169573

. Cell—Mediated Responses in Diagnosis

and Prognosis of Disease ............
Immunohematology and Blood
Banking ..........................

36
38

43

44
45

48
50

60
60

61
61

63

64
64

66
69
71

F. Tissue Typing ..................... 73
G. Diagnosis and Epidemiology of
Parasitic Diseases .................. 75
H. Serological Epidemiology and Public
Health ............................ 76
I. Immunology as Applied to Forensic
Medicine .......................... 77
J. Conclusions ........................ 77
Chapter 6. ALLERGY AND DRUG REACTIONS ............ 79
A. Immediate Anaphylactic (Class I)
Hypersensitivity ................... 82
1. Allergic sudden death ............ 82
2. Allergic rhinitis ................. 83
3. Asthma ........................ 83
4. Atopic eczema .................. 84
5. Treatment ...................... 85
B. Serum Sickness and Hives .......... 87
C. Hypersensitivity Pneumonitis ........ 90
D. Contact Dermatitis ................. 91
E. Allergic Drug Reactions ............ 93
F. Conclusions ....................... 94
Chapter 7. AUTOIMMUNITY .......................... 96
A. Mechanisms of Autoimmunity ....... 96
B. Autoimmune Disorders of Medical and
Social Importance ................... 98
1. Immune complex diseases ......... 99
a. Glomerulonephritis ............ 99
b. Systemic lupus erythematosus . . 102
c. Rheumatoid arthritis .......... 103
2. Multiple sclerosis—altered self-
antigen ........................ 104
3. Autoimmune thyroid disease—
unmasked self-antigen ........... 105
4. Drug purpura and hemolytic anemia
—normal cells affected as “innocent
bystanders” .................... 106
C. Summary and Prospectus ............ 108
Chapter 8. TRANSPLANTATION AND CANCER IM-
MUNOLOGY .............................. 110
A. Transplantation .................... 112
1. Blood transfusion ............... 112
2. Skin transplantation ........ ‘ ..... 113
3. Transplantation of the cornea ..... 113
4. Organ transplantation ........... 114
a. Kidney transplantation ........ 114
b. Heart transplantation ......... 117

0. Bone marrow transplantation . . 117

d. Liver transplantation .........
e. Lung transplantation .........
f. Transplantation of other
organs ......................
5. Special needs of transplantation . . .
B. Cancer Immunology ................

Chapter 9. THE FUTURE OF IMMUNOLOGY—ALMOST
WITHIN OUR GRASP ......................

A. Immunological Manipulations ........
1. Immunotherapy .................

a. Immunosuppression ...........

b. Augmentation ................

c. Reconstitution ................

B. Goals .............................
Cancer .........................
Transplantation .................
Infectious diseases ...............
Autoimmunity ..................
Allergy ........................
General features ................
C. Cost ..............................

Appendix A. Glossary ..............................

@P‘PWN!‘

Appendix B. TASK FORCE 0N IMMUNOLOGY AND DISEASE
—Description and Purpose ..............

Appendix C. List of Participants and Editors .........

118
118

118
118
121

128

128
128
128
129
132
133
133
136
139
142
143
144
145

149

154
156

PREFACE

In the past two decades biomedical science has made
great strides in understanding the body’s immune mecha-
nism and also how to discern those diseases that result
from an inadequate or abnormal immune mechanism.
Throughout this period of rapid developments in the field
of immunology, the National Institute of Allergy and In-
fectious Diseases has fostered and supported research in
university, hospital, and Federal laboratories and clinics
throughout the country. In the interests of communica-
tions between the researchers and the practitioners, the
Institute sponsored the Task Force on Immunology and
Disease, involving over 100 senior scientists, listed in an
appendix to this volume. The Task Force report written
in scientific language, is a review of current knowledge
on the role of immunologic processes in the cause, recovery
and prevention of disease. It reviews as well the areas
where significant knowledge is missing and thus indicates
priorities for future research.

This book contains a summary of that report and is
written in less technical language. It is intended to help
the reader to understand better his own particular im-
munologic mechanism and how it protects him from
disease or, conversely, may cause diseases ranging from
such common and annoying problems as hay fever, to
more serious and incapacitating or fatal diseases such as
asthma, lupus erythematosus, rheumatoid arthritis, and
chronic glomerulonephritis. It does as well confirm that
“an ounce of prevention is equal to a pound of cure”;
money investment in research avoids many—fold that
amount in cost of treatments. Much remains to be learned,
for there are few areas where our knowledge is adequate
to the disease challenges we face.

Dorland J. Davis, M.D., Dr. P.H.
Director, National Institute of
Allergy and Infectious Diseases

ix

 

Foreword

It is difficult for the person not intimately involved in
the actual practice of immunology to comprehend the
broad scope and potential of this discipline. Perhaps the
greatest barrier is in the name “Immunology” itself.
The term immunity, from which the name of the science
was derived, was originally coined to convey the concept
of the freedom or exemption of the individual from infec-
tion. Now the area encompassed has become so broad that
numerous sub-classifications such as tumor immunity,
transplantation immunity, clinical immunology, autoim-
munity, and immunohematology are commonly used; the
overall unifying concept is the ability of the individual
to distinguish between normal self and nonself and to re-
act specifically to the attribute of foreignness. The po-
tentials of the science appear virtually unlimited as they
encompass the full range of responses of the individual
to his environment, and extend in changing ways from fe-
tal life to the extreme of old age, possibly even being
responsible for much of the process of aging itself.

The reader should realize that this is a parochial re-
port, confined to “American” thinking and mainly the
“American” scene. Most of the scientific activities dis-
cussed, plus the costs and statistics cited, relate to the
U.S.A. The science and disease situation in other coun-
tries may be similar or dissimilar and, in general, were
not considered in the Task Force activity.

xi

 

Chapter 1. THE OLD AND THE NEW
IMMUNOLOGY

A. Early History of the Science of Self

Immunology began long before anyone knew of the ex-
istence of microorganisms or the immune system which
protects the body against infection. In ancient Greece,
Thucydides recorded that during the plague of Athens
only those few who had had the disease and recovered
from it would nurse the sick, since it was known that no
one ever caught it a second time. While the phenomenon
of immunity was Widely recognized for thousands of
years, it was not until the 15th century that the Chinese
and Arabs converted the knowledge into clinical treat-
ment by infecting persons with material from the pustules
of smallpox patients to induce immunity by giving them
a mild form of the disease.

In 1796, Edward Jenner, an English physician, using
a lancet, inoculated an 8-year-old boy with fluid from a
milkmaid’s cowpox pustule in an attempt to give him pro-
tection against the more virulent smallpox. Jenner knew
nothing about the immune system but he had observed
that milkmaids Who contracted cowpox from cows rarely
contracted smallpox. The experiment proved successful—
the immunity against the disease was established; the
practice of vaccination was born. (It is called vaccination
because the immunizing disease material came from the
cow; vacca in Latin.)

It was not until a century later, however, when Louis
Pasteur formulated the germ theory of disease, that sci-
entists began to suspect that the body possesses a defense
system for recognizing and combating disease agents.
Although, as the founder of bacteriology, Pasteur was in-
terested in the nature of microorganisms, he was much

1

 

Fig. 1. With the joint assistance of WHO and UNICEF more than
150 million people have been vaccinated in 61 countries.

more concerned with preventing the diseases they caused.
By developing attenuated and killed vaccines—cultures of
the organism that possess the same immunological char-
acteristics, but that have been weakened or altered in such
a way that they are less virulent and dangerous—Pasteur
became the first great experimental immunologist. His
contributions in this field, including the development of
rabies vaccine, marked the beginning of modern scientific
immunology (Fig. 1).

By 1900, many of the principal mediators of immunity
had been identified: wandering phagocytic (scavenger)
cells; antibodies with the ability to specifically neutralize
toxins such as those of diphtheria and tetanus; and that
group of substances in the blood and body fluids called
complement which acts in concert with antibodies as
“helper” agents in the body’s defense against infection.
Antibody formed in response to immunization was found
to be specific—tetanus antitoxin does not protect against
diphtheria—and specific immunity could be transferred
by transferring serum containing antibody from an im-
mune to a nonimmune individual. Full awareness of the
role of cells of the lymphoid system in immunity came
much later and developed over a period of years.

While it was shown in these early experiments that the

2

body is capable of producing specific antibodies in re-
sponse to the invasion of disease-causing agents, it was
not until the 1940’s that it was finally recognized that a
poorly functioning immune system, or the absence of one,
can leave the body virtually defenseless against infection
from without or malignancy from within.

In the early part of the present century, it was recog-
nized that a variety of allergic diseases are immunologic;
these include common ailments such as hay fever and
poison ivy. The statement that they are immunologic
means that they result from immunization, that these
diseases can be transferred by transferring serum or im—
mune cells from an allergic to a normal individual, and
that they are specific—a person who gets hay fever or
asthma when he inhales ragweed pollen does not react to
timothy (unless he is also allergic to that). Here the origi-
nal purpose of antibody to protect against infection is, as
it were, perverted. Here, reaction of antibody with anti-
gen (pollen) is harmful to the tissues and produces
disease.

This illustrates the ambivalent character of most im-
mune reactions. They protect us against severe infection
and even death in some cases, while in others they produce
diseases of their own. In the case of hay fever or asthma,
where no infection threatens, most disease is an unfortu-
nate by-product of an otherwise useful protective mecha-
nism. The study of immunologically mediated disease is
today conducted within the broad disciplines of clinical
immunology and immunopathology.

The discovery at the turn of the century by the great
scientist, Karl Landsteiner, that there are at least three
main blood groups in humans (A, B, and 0), showed that
immunologic reactions can involve tissues as antigens.
Red blood cells of one individual have different antigens
on their surface than the red cells of another. Conse-
quently, a blood transfusion with the wrong blood type can
result in an immune reaction called a “transfusion reac-
tion” (Fig. 2). It represents an unfortunate class of im-
munologic disease because the disease results from the

3

 

Fig. 2. Transfusion of a patient with animal blood. (From Scul-
tetus, courtesy of the National Library of Medicine.)

doctor’s treatment. However, there is a naturally occur-
ring equivalent which results when a mother becomes im-
munized against red blood cell antigens which her unborn
baby has inherited exclusively from the father and which
are foreign to the mother. This is the well-known Rh dis-
ease or erythroblastosis, also called hemolytic disease of the
newborn. Blood Banking, which makes use of refined tech—
niques to distinguish red cell antigens, is a valuable ap-
proach to both theoretical and applied problems in this
field. Today, it is possible to carry out transfusions at will,
without fear of complications, and to prevent completely
hemolytic disease of the newborn. Numerous diseases of
the blood are now known to be immunologic and can be
diagnosed, and in many cases, treated by suitable im-
munologic means.

Early in this century, that great German scientist,
Paul Ehrlich, observed still another characteristic of the
immune system. He noted that one usually does not pro-

4

duce antibodies to one’s own body constituents. Ehrlich
showed that this trait, now called self-tolerance, is a criti-
cal balancing feature of the immune system, preventing
the continual initiation of autoimmune diseases. Forty
years later, the American immunologist, R. D. Owen, pro-
vided an experimental basis for the principle of self-
tolerance in observing that non-identical cattle twins
which share blood streams up to the time of birth are in-
capable of making an immune response against their non-
identical twin. Following this lead, a British team headed
by P. B. Medawar showed that one could deliberately in-
duce specific tolerance to foreign skin grafts by exposure
of fetal animals to foreign lymphoid cells. Animals made
specifically tolerant to skin grafts from one type of donor
could still readily reject grafts from unrelated donor
types. Moreover, graft rejection was caused by immune
lymphoid cells. These discoveries, demonstrating that re-
jection of skin grafts is immunologic in nature, resulted
in the Nobel Prize to Medawar in 1960 and subsequently
set the stage for later experiments in human organ
transplantation.

In recent years, there has been a rapidly growing in-
terest in transplantation or grafting of tissues such as
skin and bone marrow, and organs such as the kidney and
heart. Here, again, there are tissue antigens that differ-
entiate one individual from another and frequently lead
to immunologic rejection of a graft. The solution to the
problem of transplantation is in part genetic, and there
is a need to learn the inheritance of these antigens. In
part, it requires better tissue—typing techniques analogous
to, but far more complex than, the well-established tech-
niques of blood grouping and matching. In part it requires
better understanding of the immunologic mechanism
known as rejection. These constitute the main focus of
current transplantation research. As a result of recent ad-
vances in these areas, transplantation of certain organs,
notably kidneys, has become a relatively safe and largely
successful procedure.

We now know also that most human cancers have

5

unique antigens, which can be recognized as “foreign” yet
fail'to be rejected by the cancer patient. The existence of
a cancer-specific immune response, tumor immunity, has
opened up a new and powerful area in medicine, immuno-
therapy. Immunotherapy seeks to cure disease by boost-
ing an inadequate immune defense or by controlling an
over-exuberant response.

B. The New Immanalogy—Accomplishments
and Applications

The initial advances in microbial immunity made by
Pasteur, Koch and the other founders of microbiology were
paralleled by Landsteiner’s description of blood group
antigens and his studies on the specificity of serological
reactions (which founded the science of immunochemis-
try), and the delineation of the role of antibodies in a1-
lergic reactions by Arthus, Dale and others. Immunology
then assumed a relatively steady and undramatic progress
in the period from 1900 until World War II. Under war-
time conditions, however, answers were rapidly required
to many urgent problems, and a great impetus was given
to such diverse topics as blood banking and blood trans-
fusion, skin grafting for the treatment of burns and im-
proved mass prophylaxis against gas gangrene and
tetanus. This impetus was maintained at the end of the
war by the encouragement given by the National Institutes
of Health, and by other funding agencies in the US. and
abroad. Many new immunologic study subdivisions were
developed and each line of investigation was broadened
extensively. At the same time, many of the new findings
began to be applied to clinical problems. By the late 1940’s
immunology ceased to be simply a technology of preven-
tive medicine and became instead a major discipline of
basic science, touching upon an ever-widening range of
practical medical problems in the fields of infectious dis-
ease, allergy, autoimmunity, maternal-fetal relations,
transplantation, and cancer. Today, it affects every branch
of medicine except, perhaps, psychiatry.

6

With the discovery of sulfonamide drugs, and soon
thereafter of penicillin and a host of other antibiotics, it
appeared that many of the life—threatening problems of in-
fectious diseases had been solved. The drive to develop
new vaccines or antisera faltered. Sulfonamides and
antibiotics did not, however, solve all the problems and
sometimes they created new ones. Many viruses and fungi
are insensitive to antibiotics and drug—resistant bacteria
are continuing to evolve. A small but significant propor-
tion of patients treated with antibiotics become sensitized
to the drug or develop bone marrow failure. Thus, empha-
sis has again returned to augmenting our defense against
infection by immunological means.

Even though progress in developing new vaccines was
slow, other developments in immunology continued. One
of the most important, not only to the immunologist but to
many other fields of science, was the realization that
lymphocytes could be activated to perform a variety of
biologic functions. Most of the present-day immunology
and much of pathology, genetics, and biochemistry is de-
voted to studies of lymphocyte differentiation and func-
tion. This knowledge forms the basis for an exciting new
branch of science, cellular immunology. Extremely potent
new weapons for the treatment of many diseases are de-
veloping from these studies. The claim that the prevention
and treatment of such dread diseases as cancer, heart dis-
ease and stroke, may be problems for solution by the
immunologist, may seem to be extreme, but past accom—
plishments of immunology are so impressive that its
forward projections, especially those based on cellular
immunology, must be seriously weighed.

Solved, or largely solved, are the difficulties of safe
blood transfusion. Elimination of Rh disease, diphtheria,
smallpox, poliomyelitis, and pertussis, and the trans-
plantation of kidneys and bone marrow from carefully se-
lected donors, are but a few of the solid and proven
accomplishments of the immunologist.

Immunological procedures form the basis for the inex-
pensive, rapid (and sometimes the only means of) diag-

7

nosis of an expanding number of diseases. Immunologic
techniques have been adopted by the biochemist for iden-
tification of materials in trace quantities, by the forensic
pathologist in the identification of blood stains, by the
physiologist in studying transport of ions across cell mem-
branes, by the radiologist in assessing the safety margins
of his radiation therapy, and by the obstetrician in the
early diagnosis of pregnancy. These are but a few of the
uses of immunological probes and procedures in other
fields.

A prime example of the practical application of basic
immunologic knowledge is provided by organ transplanta-
tion. Studies in animals, which showed that graft rejec-
tion is immunological and which initiated an analysis of
its mechanism, led to a formulation of the genetic laws of
transplantation and to the powerful techniques of im—
munosuppression to prevent rejection. These, in turn,
made possible kidney transplantation for thousands of
people each year. Three-quarters of these recipients can
return to normal or near normal life. Application of the
same principles has led, in the last five years, to the first
successful grafts of bone marrow, a highly desirable tech-
nique for the treatment of leukemia, and for the treatment
of a variety of deficiency diseases, congenital or acquired.
The full potential of this form of immunologic manipula-
tion has yet to be realized. It awaits perfection of pro—
cedures for avoidance of rejection.

A second example, relating to immunization against
poliomyelitis, illustrates the economic benefits derived
from the practical application of basic immunologic
knowledge. It is estimated that in the first seven years
after introduction of the Salk vaccine, in the United States
alone, the vaccine prevented approximately 154,000 cases
of poliomyelitis and thus spared 12,500 deaths, plus 36,400
severe and 58,100 moderate cases of lasting paralysis. The
tremendous gain to society in human terms was matched
by a striking saving in hospital beds, respirators, etc.,
which were no longer needed, and by the productive man-
days of labor saved by the polio vaccine. The entire cost

8

of developing, producing and administering the vaccine
was less than one-tenth of the amount saved. Comparable
savings have, of course, become worldwide and may rea-
sonably be expected to continue over an indefinite future
period.

These illustrations can be matched by many others, and
one may reasonably expect equally exciting successes in
the fields of allergic and rheumatic diseases, and, perhaps,
even in the treatment of cancer. Far from having run its
course, immunology presents challenges in the intellectual
sphere while promising major advances in the practice of
medicine and its specialties. The potential value of these
to society, whether measured in human terms or reduced
to a conventional dollars-and-cents statement, is incal-
culable. These accomplishments are based upon great
technological and conceptual advances, stemming from de-
velopments throughout the century, but showing a true
acceleration during the past 20 years. The growth of
knowledge was coincident with public awareness and en-
thusiastic support of the contributions of research to
medical treatment. It was consequent upon the recruit-
ment of eminent scientists from other fields and upon the
emergence of young, energetic and highly trained new
investigators.

\nkl

Chapter 2. THE IMMUNE RESPONSE

The immune system is extremely complex and is widely
dispersed through most of the tissues of the body (Fig.
3). Its basic constituents or effectors are lymphocytes
(small white cells that are normally present in the blood
and in lymphoid tissue), antibodies (protein molecules
that are produced and secreted by some lymphoid cells),
and a variety of phagocytic cells (scavenger cells fixed
within the tissues or transported in the blood (Fig. 4).
Lymphocytes have the remarkable and unique ability to
recognize foreign substances that invade the body, or that
develop from within it. Aided by antibodies in the blood-
stream, their function, and that of the phagocytes, is to
patrol the body and to guard it from any such potentially
harmful agents. They constitute a nearly perfect surveil-
lance team that has evolved from more primitive systems
as far back as the earliest vertebrates.

When a foreign substance, such as a bacterium, virus
or tissue from another individual, is introduced into an ani—
mal 01 human, that individual responds by (1) producing
antibody molecules which specifically bind the introduced
su s ances (this constitutes the linmmal immune 7e-
spo7i3e§ and by (2) mobilizing cells which can specifically
cmmniie response).

Thus, in essence, there are two main classes of immune
response. Let us examine the mechanisms that mediate
them.

A. Antigens and Antibodies

Any substance which provokes an immune response
when introduced into the tissue of an animal or human is
referred to as an antigen or immunogen. Antigens ca-

10

COMPONENTS OF THE IMMUNE SYSTEM

     
  
  
  

Eyes, Nose , Mouth

(secretions Tensile and Adenoids

Respiratory Tract, Thymus

Mammary Glands Lymph Nodes

Sp\e.en

Gast r0 — Inteslc \ flat Payer ‘5 Patches

Tract

Gen'Ltour'mary Traci Appendix

Bone Marrow

Fig. 3. The major structures of the immune system are indicated
to the right; some of the systems they guard are on the left.
(Modified from Bellanti, Joseph A., Immunology, W. B.
Saunders, 1971.)

pable of stimulating an immune response have two func-
tional regions: one is called the antigenic site, or hapten;
the other is called the carrier.

Antibodies recognize antigens through surface charac-
teristics of the foreign substance, especially by the electric
charge, or by the pattern or shape. T0 unite with the anti-
gen, the antibody must be precisely the right kind or
specific.

As a rule, antibodies are made onlyrin response to the
entry of a particularantigen into the body. Just as mil—
lions of different antibodies are reduired to cope with the
infinite variety of possible antigens, the lymphoid‘xsystem
includes many different lymphocytes, each capable of re-

11

T— ly@mphocy+es B—lymplnocylzes

+An‘lZI sen .
? + Macrophage + Antigen
(9‘

@ 33%) 31’? @@ {\ Efieckor

@

 
 

Blast
Cel ls

s):

\o
>—

0‘
90

 

 

Killer Activated Prlmed Plasma cells
lympl‘oblast macro phage. anl: ‘39—” gel ls
Sensl'lilve
cells
Cell — medlated l-lumoral
immunity Memory immunity

Fig. 4. The Genesis of an Immunological Reaction. Antigen is
processed and activates sometimes T, sometimes B and some-
times both types of lymphocytes. As a result of exposure to
antigen, some cells become primed and respond more rapidly
to subsequent exposure. This is immunologic memory. Acti-
vated B cells often convert into plasma cells which secrete
antibodies and thereby provide humoral immunity. Activated
T cells react in Type IV (delayed hypersensitivity) reac-
tions by their direct participation as killer or effector cells.
They also release substances called mediators which increase
blood flow and the flow of fluid into the tissues, and affect the
performance of other cell types including macrophages.
(Modified from Davis, B. D., et al., Microbiology, Harper and
Row, 1973.)

acting to its own specific antigen. Vaccination is nothing
more than the injection of antigens that have been ren-
dered harmlessmeyw or attenuated) into the body,
st timulating the lymphgjtes to produce antibodies against
themus, the immune system is able to respond
smw t0 the antigen on an organism such as mea-
sles virus by producing large numbers of antibody mole-
cules and cells capable of binding and destroying the

12

invader. The response would not protect against unrelated
organisms like mumps or polio. Furthermore, once,.an.in-
dividu‘al has been immunizedutoman antigen, the immune
system responds much more rapidly when the same anti-

en enters the body a‘second time. This factor, known as
immunologic memory; accounts for the long term protec-
tion or immunity characteristic of an individual who has
had certain forms of infectious diseases or who has been
vaccinated against such a disease.

B. Cellular Events in the Immune Response

When antigen is introduced into the body intentionally,
as in immunization for the prevention of disease, or un-
intentionally, as in infection with a bacterium, some of it
is trapped by phagocytic cells called macrophages which
have the capacity to break down or digest the antigen. A
portion of the antigen remains on the surface of these cells.
In this location, the antigen comes in contact with a type
of small White blood cell referred to as a lymphocyte,
which is then stimulated (see below). These lymphocytes
have on their surface, molecules (receptors) which can
bind the antigen specifically in the sense that a given key
fits a given lock.

C. Thymus-derived (T) Lymphocytes

Recent research has shown that there are two broad
classes of lymphocytes. One type is a cell which originates
within the bone marrow, but which migrates through the
blood and settles in the thymus, a unique lymphoid organ
found at the base of the neck. In this location the cell ma—
tures and gains the ability to carry out certain functions.
At the conclusion of this maturation period, the cell leaves
the thymus and circulates throughout the body. Because
of this period of residence within the thymus, this cell is
called a thymus-derived (T) lymphocyte (or T cell). The
T lymphocytes are responsible for many of the cellular

13

immune responses. When they encounter the antigen for
which their receptors are specific, they are stimulated to
divide so that many more T lymphocytes of the same
specificity are produced. In addition, they appear to
change in character and acquire the ability. to perform at
least three different tasks: 7(1) they can interact directly
with the antigen, as when the stimulated (“killer”) T cell
reacts with and dest1oys a virus-infected cell or a fo1e1gn
tissue or tum01 cell, (2) they can produce yarious sub-
stances (called mediatms or lymphokines), some of which
can att1 act or activate other components of the immune
syStem, while othe1 mediators act directly, and (3) they
can act as “helper ” cells which inte1 act With the other ma-
jor type of lymphocyte (B lymphocyte) to enable“ the latter
to pioduce antibodies. T lymphocytes, obviously, playa

crucial central role in the bodily defense mechanisms.
Consequently, infants born with a deficiency in the T lym-
phocyte system (for example, a congenital absence of the
thymus) are very subject to serious infectious diseases
and they die in infancy. In addition, individuals with a de-
ficiency in the function of their T lymphocytes have an
increased frequency of many types of malignant tumors.

D.‘ Bone Marrow-derived ( B ) Lymphocytes and
Cellular Collaboration

The other major type of lymphocyte is the B lympho-
cyte (or B cell). This cell also originates in the bone mar-
row, but it matures in sites other than the thymus. When
a mature B cell encounters the antigen for which it has
specific receptors, it is stimulated to divide and differen-
tiate into plasma cells» which can produce large numbers
of antibody molecules. These antibodies show the same
specificity as the B cell receptor; that is, they bind the
same antigen.

Recently, it has become clear that the mere exposure of
a B lymphocyte to a foreign antigen rarely leads directly
to the development of antibody forming cells. Rather, B
lymphocytes must interact with the specificyi‘helperVE

14

lymphocytes alluded to above. This interaction is called
Samarétaperation or T 'cell: B cell collaboration. The
discovery of this collaboration has virtually revolutionized
research in immunology since it has opened the door to
manipulation of discrete segments of the immune response.

E. Tolerance and Autoimmunity

One of the hallmarks of the immune system is its abil—
ity to discriminate between foreign antigens and its own
“self” constituents. This lack of responsiveness to self an-
tigens is called self-tolerance (Fig. 5). In some individuals
this tolerant state may be circumvented and an individual’s
own constituents may act as an antigen, eliciting a highly ‘
destr 11ct1ve immune 1esponse to his own tissues. The
lesult of this 1s the development of autozmmumty or self-
an768810n (Chapter 7). Under the approp1iate condi-
tions, it is possible to experimentally induce tole1ance to
many foreign antigens; this unresponsiveness has been
shown to exist in both T and B lymphocytes. Studies in
experimental tolerance induction have thus provided mod-
els for the development and control of autoimmunity.

F. Regulation of the Immune Response.

It is now clear that the immune system is subject to
several control mechanisms. One method of regulation is
via the B cell product or specific antibody. The injection
of antibody prepared in another individual interferes
with the development of immunity to the cor responding
antigen. For example, the antibody response to the Rhfac-
tor on human red blood came suppressed if specific
Rh antibodies are given at the time of exposure to this
antigen. This is p1ecisely the principle and treatment
M to prevent an Rh negative mother from producing
antibody against the Rh red blood cell antigen after she
delivers an Rh positive baby. In a related manner, spe-
cific antibody has been applied to control graft rejection in
human and animal transplantation, in this case the im-

15

91

Death Death Death
Before Birth
After Birth

Fig. 5. Induction of tolerance to self-constituents (SI—83) by selective elimination of lymphocytes with self-react—
ing surface receptors. These cells are either killed or inactivated. Surviving cells are able to react only with
non-self (NS) foreign antigens of specificity NSl, N82, N83, etc. As originally postulated by Burnet, elimina-
tion of self-reactive cells occurs before birth. (Modified from Roitt, I. M. in Essential Immunology, Blackwell,
1974.)

AN IMMUNOGLOBULIN MOLECULE

 

 

 

 

 

 

ANTlGEN
BINDING
HEAVY 5m":
CHAIN
UGHT CHAlN
‘93
9 *3-8—4 2
N U HINGE REGION
('7 m

 

 

 

 

 

 

Fig 6. Prototype structure of an antibody or immunoglobulin
molecule (IgG class). (See text for explanation.)

munological unresponsiveness is called enhancement. -An-
tibody also has been implicated in preventing tumor
rejection (Chapter 8), the antibodies involved are some-
times called blocking and sometimes enhancing antibodies.
Another method of regulation is through T cell activity.
T suppressor cells are formed in the spleen after immuni-
zation and appear to regulate both T cell activity and an-
tibody formation. Understanding the regulation of the
immune response, as well as the dichotomy of T and B
cell function, has had enormous impact for the possible
manipulation of the immune system (Chapter 9).

G. Structure of Antibody Molecules

Antibody molecules (or immunoglobulms), the products

17

of B cells, are proteins which are made up of two types‘ of
cham acids (Fig. 6). One chain is approxi-
mately twice asiojlg as_ the other and 1s referredm as a
heayyiichaing the other chain 1s termed the light (L)
c ain. The prototype antibody molecule consists of tthi
afléjmmnswhich are held to each other primarily
through bonds made by linking two sulfur atoms (disul—
fide bonds). One end of an H chain together with the cor-
responding end of an L chain of an antibody forms the
site which specifically binds the antigen , (active site).
Thus, the prototype antibody molecule, consisting of two
H—L pairs, has two active sites and so can bind two mole-
cules of antigen. Detailed knowledge of the structure and
sequence composition of immunoglobulins has greatly aug-
mented our understanding of how these molecules are
synthesized and how they function. (The Nobel Prize was
awarded to Drs. Porter and Edelman for their research
in this area.) It is now known that each chain consists of
a large region which is amazingly constant in different
types of immunoglobulins even from unrelated species
(constant region). There is, on the other hand, another
region (variable region) which is highly variable and
seems to determine the diversity of specificities which
immunoglobulins possess. The variable region is believed
to include the active site. These regions are illustrated
below with several words, part of which are constant and
some of which vary (in letters, or amino acids) :
V—A—C—C-I—N—A—T—I—N—G O—S—C—I—L—L—A—T—I—N—G
V—A—C—C—I—L—A—T—I—N—G U—N—C—O—L—L—A—T—I—N-G
Thus, the final A—T—I—N—G represents the constant por-
tion, and the first five to six letters, the variable section
which provides for antibody (word) specificity.

H. Immunoglobulin Classes and Their Function

In humans there are five major classes of antibodies
(or immunoglobulins) which differ slightly from each
other in the constant region of the H chain. In addition,
some of these classes consist of multiples of the two H and
two L chain structure of the prototype. Of the five differ-

18

ent major classes of immunoglobulins, four have known
separate and important biological functions. For example,
1mmunoglobu11n G (IgG) is known to promote the more
efficient uptake, removal and destruction of invading mi-
croorganisms by macrophages and other phagocytic cells.
This class of immunoglobulin enters tissue spaces and can
pass through natural barriers like the placenta. Another
class ”QM, which 1s formed early 1n response to antigen,
is considerably larger and tends to remain in the blood
stream. Both of these classes of antibodies, upon combina-
tion with their specific antigens, can bind and activate a
complex and exquisitely potent series of blood enzymes
known as the complement system The latter can act to
destroy the antibody- bound invader (see below). A third
major class of immunoglobulin is IgA, which is concen-
trated in the fluids of the respiratory and gastrointestinal
system, where it acts as a first line.,of.defense...&Lg§:1,.'11.1st
invading 01 ganisms IgE, the fourth class for which a
function is known, attaches itself totthe surface of cells
known as basophils or mast cells. When this cell- bound
IgE encounters its appropriate antigen, the resulting
binding causes the release ofpowerfulmolecules ..... like
histamine, which, in turn, produce thesymptomsiofflal-
lergies ( see Chapter 6).

It can be seen then that antibodies bind the antigen for
which they are specific and that this binding results in a
series of events which may lead to the destruction of the
foreign substance or, under certain conditions, to harm
the individual mounting the response (e.g. an allergy). It
seems logical to refer to the protective aspects of the im-
mune response as immunity (exemption from disease),
while the damaging aspects of the immune response to the
host are referred to as hypersensitivity (excessive sensi—
tivity).

I. Accessory Systems: Complement

How, then, are the protective and damaging aspects of
the immune response mediated? Both immunity and hy-
persensitivity are augmented by the engagement of other

19

 

Fig. 7. Structure of Complement Lesion depicted in schematic
form. The structure is believed to consist of the five late-acting
complement components C510, C6, C7, C8, and C9. These com-
ponents are thought to attach themselves to the lipid bilayer
of the cell membrane. The complement components, which are
proteins, are believed to assemble themselves into a doughnut
or a funnel shape that penetrates the bilayer. The hollow core
of the structure could form the lesion through which water
and ions flow into the cell until it bursts. (From Mayer, M.
Scientific American, November 1973, reprinted with permis-
sion.)

potent non-specific bodily defense mechanisms. One of
the most important of these is the complement system, a
complicated group of proteins which react in a predeter-
mined sequence. Classically, when antibody of the proper
class (IgG or IgM) binds to the antigen for which it is
specific, the complex which is thus formed binds (fixes) a
protein called the first component of complement (C1).
In turn, bound C1 binds and activates additional compo-
nents with unique enzymatic activities, in the order C1,
C4, CZ, C3, C5—C9.

The classic activity of complement and one that has

20

been studied for many years is the breakdown (lysis) of.
antibody coated red blood cells. In the final stage of com-
plement activation, 09 and some of the previously acti-
vated components form a complex on the cell surface and,
by punching a hole in the cell membrane, lyse the anti-
body coated cell (Fig. 7 ).

This is not the only attribute of the complement system.
The activation of some of the intermediate complement
components results if the antigen is on the surface of a
bacterium or other type of cell, and the binding of the
complement system may cause the direct destruction of
that cell.

Another consequence of complement activation is the re-
lease of small molecules (mediators) which have powerful
effects on blood vessels. The affected vessels become leaky
and the area becomes inflamed. The mediators also attract
and activate white blood cells. Finally, it should be noted
that activation of some components of the complement sys-
tem can be triggered nonspecifically, often by bacterial
products.

Thus, the complement system provides a powerful aux-
iliary defense mechanism. However, sometimes complexes
of antigen and antibody are formed or become trapped in
certain critical regions, such as the kidneys or the linings
of the blood vessels. In this event, the continued activation
of the complement system and the consequent produc-
tion of molecules leading to responses of inflammation may
cause serious damage to these tissues and lead to major
disorders, such as glomerulonephritis and arthritis (see
Autoimmunity, Chapter 7).

The Immune Response

This brief discussion of the structure and mechanisms
of the immune system sets the stage for a more thorough
exploration of the science of immunology and how the im-
mune system may prevent disease or, alternatively, how
it may cause or aggravate disease. The immune system
has enormous power and complexity. Its power makes it
a formidable weapon for the physician in his attempt to

21

control disease and also a serious adversary When it
causes disease. Its complexity provides the opportunity to
regulate it in many ways—an opportunity that is in di-
rect proportion to the depth and precision of our under-
standing of its function. There is still much. to be learned
about the immune system.

22

Chapter 3. BIOLOGY OF THE IMMUNE
SYSTEM: REPRODUCTION, NORMAL
AND ABNORMAL DEVELOPMENT
AND AGING

Normal and aberrant immunological responses affect
all stages of human life. In this chapter, the effects of the
immune system in reproduction, during development and
in the process of aging are discussed, as are the conse-
quences of deficiencies in immune responses.

Immunological problems may precede the birth of an
individual. For example, it is suspected, although un-
proven, that immunization of a woman by her husband’s
spermatozoa or seminal plasma, or her sensitization to an-
tigens of the trophoblast, a part of the placenta, may be
related to infertility or abortion.

The process of gestation itself is an immunological
paradox: an incompatible graft—the fetus—is carried to
term and normally delivered without immunological dam-
age. The development of the fetus is regulated by surface
structures on the cells of the early embryo: how these
difier from or are similar to the surface structures which
immunologists call antigens, and how this regulation dur-
ing differentiation relates to the immunological system
are questions just beginning to be asked.

Important advances are being made through the study
of teratomas. These are tumors of reproductive tissue that
represent a given stage of embryonic development. It ap-
pears that these tumors perpetuate antigens that are
normally expressed only transiently in the fetus. Thus
embryology may lead to an understanding of tumor devel—
opment and to knowledge of tumors corresponding to
different stages of the embryo, as well as give valuable in-
formation about fetal developmental stages.

The fetus is normally protected by the maternal im-

23

mune system and by the placental barrier. These defenses
may fail to protect against some types of infections, and
the fetus may be damaged not only by the infectiOn but
by the maternal and/or fetal immune response to the in-
fectious agents. Improper development of the fetus from
such varied causes as inherited abnormalities, intrauter-
ine infection or the effects of certain drugs, may lead to
failure of proper development of the immune system and
hence to immunological deficiency. The possibility that
more subtle degrees of failure can later lead to autoimmu-
nity, allergy and hypersensitivity, and to malignancy is
suspected. Finally, the fetus may be subjected to the assault
of the maternal immune system against fetal antigens;
the best known example of this is Rh incompatibility,
which may lead to death of the fetus in utero or to hemo-
lytic disease at its birth. Incompatibility for blood group
A may occasionally lead to damage or death of the fetus or
newborn.

The newborn infant enters a highly antigenic world
with some degree of immunity conferred by placentally
transferred maternal antibodies. The extensiveness of
the maternal experience with antigens determines the
completeness of that protection. The newborn infant,
therefore, is most likely to be threatened by infections to
which the mother has not been exposed.

As passively transferred protection wanes, the child
may experience frequent infections if his own immune
system cannot respond appropriately; such a failure of
the immune system can lead to death. Childhood can also
bring an increased incidence of certain types of tumors.
Children with some forms of immunodeficiency are espe-
cially at risk of developing tumors.

In late childhood and early adulthood, the immune sys-
tem serves its protective function most successfully.
Through prior exposure to specific or cross reactive anti-
gens, immunological memory of the individual is well de-
veloped; infections or impairment of the immune system
are only rarely problems during those ages, although epi-
demics of infrequently encountered diseases remain a

24

constant but remote threat. Ironically, this well developed
immune system also subjects most, if not all, individuals,
at some time in their lives, to allergic or hypersensitivity
reactions.

As the immune system ages and fails, man is again sub-
ject to infectious disease and the Vissicitudes of malig-
nancy and autoimmunity. Indeed aging itself is perhaps
largely a failure of the immune system.

A. Immunology of Reproduction
l. The maternal-fetal relationship

A central immunological problem of reproduction is
posed by the realization that the fetus contains antigens,
inherited from the father, which are foreign to the ma-
ternal environment in which the fetus must develop. Fol-
lowing the union of sperm and ovum, the human embryo
invades the foreign soil of the highly vascular uterus and
establishes a complex parasitic relationship. Recent stud-
ies suggest that the continuing maternal acceptance of
this foreign graft is a result, at least in part, of the for-
mation of substances by the mother which are capable of
blocking her own cellular rejection response against the
fetus. The exact role of such blocking factors is not
known, but their induction appears to be caused by a
basic immunoregulatory mechanism generally operative
against tumors, against transplants, and sometimes even
against self components. Women Who have repeated spon-
taneous abortions are thought by some immunologists to
manifest failure of this normal acceptance of the foreign
graft, i.e. the fetus. The immunologic techniques to study
this problem are only now becoming available.

Choriocarcinoma, a placental malignancy often suc-
cessfully treated with cancer chemotherapy, is a disease
that might be influenced by immunological mechanisms,
since the placenta shares with the fetus the distinction of
being foreign to the mother. Thus, treatment and preven-
tion of this disease, through immunological means, are
realistic possibilities.

25

Toxemia of pregnancy is another disease with immu-
nologic overtones. This condition most frequently affects
teenage females of lower socio-economic status who are
pregnant for the first time. Its clinical symptoms are hy-
pertension (high blood pressure), edema (swelling) and
proteinuria (presence of protein in the urine). If un-
treated, it progresses to the condition known as eclampsia
which is characterized by convulsions. Antibodies may
develop against structures in the placenta and the pla-
centa itself is characteristically enlarged. A similar dis-
ease can be induced in rats. It is noteworthy that various
women who have experienced toxemia during the first
pregnancy rarely suffer from the disease during subse-
quent pregnancies. An immune mechanism for blocking a
subsequent toxemic response is suspected.

2. Immunization resulting from maternal-fetal exchanges

The brilliant analysis of Rh hemolytic disease of the
newborn (HDN) in man has indicated that the risk of
maternal immunization throughout pregnancy is not of
mere academic interest. As a result of appropriate re-
search, the prevention of HDN now is a routine part of
medical care (Fig. 8). Incompatibility for another anti-
gen, Xg“, causes a decrease in the proportion of female
infants born. It is also apparent that not only red blood
cells, but also White cells, blood platelets, antibodies and
possibly other blood components from the fetus may enter
the maternal circulation and sensitize the mother, with
resultant disease, such as lack of granulocytes, in a small
but increasingly well characterized group of newborn in-
fants. As a result of immunization by fetal tissues, at least
20 percent (probably many more) of pregnant women de-
velop easily detected antibodies to some of the major
histocompatibility (HLA) or tissue antigens. Whether
these antibodies are protective, detrimental, or inconse-
quential, is not known at present. While there is no in-
creased frequency in the amount of HLA antibodies
following induced abortion, such antibodies are commonly
found in women with severe obstetric problems.

26

Rho negative
"STIMULUS"

 

M

Fig. 8. Schematic representation of the pathogenic mechanism of
hemolytic disease of the newborn. (From Zmijewski, I mmuno-
hematology, 2nd Edition, 1972. Courtesy of Appleton-Century-
Crofts, Publishing Division of Prentice-Hall, Inc., New York.)

In a converse situation, the introduction of maternal
lymphoid cells into the fetus, results (in experimental ani—
mals) in a condition termed “wasting disease of the new-
born,” (in which the introduced maternal lymphoid cells
respond immunologically to the newborn). Mice inoculated
with maternal lymphoid cells and manifesting a similar
disease (graft-versus-host disease) show a high inci-
dence of tumors of the lymphoid system. Scrutiny of hu—
man infants Who have failed to thrive has revealed some

27

Fig. 9. Agglutination of human sperm by antibody. (a) Head-to-
Head agglutination. (b) Tail-to-Tail agglutination. (From
Rumke, First International Symposium on Immunopathology,
P. Grabar and P. Meischer, eds., 1959, Schwabe, reprinted

with permission.)

28

 

individuals with evidence of maternal lymphocytes in
their circulation. It is therefore believed that the experi-
mental situation may have a human counterpart and that
the high incidence of acute leukemia in childhood may be
a consequence of the transplacental passage of maternal
lymphoid cells. Methods for accurately studying the pas-
sage of white blood cells across the placenta have recently
been developed. The procedure is based on fluorescent
staining of antibodies to HLA antigens. Automated sepa-
ration of labeled cells will permit more detailed study.

3. Anti-sperm, anti-seminal plasma, and anti-placental
antibodies

The exposure of the female genital tract to millions of
spermatozoa, which are genetically alien cells suspended
in a complex protein material called seminal plasma, may
under some conditions stimulate antibody formation. This
could account for some cases of infertility in women, for
in certain cases, antibodies against seminal components
are persistently detectable in the serum of the woman and
in her cervical mucus (Fig. 9). Study in this area may
have a dual reward; discovery of a way to prevent this
response could reduce infertility and, at the same time,
development of an approach to actually sensitize women
against compOnents, especially certain enzymes of their
husband’s spermatozoa, could evolve into a means of
“contraception by vaccination.”

The demonstration of organ-specific and species-
specific antigens of the placenta, and the experimental
evidence in animals that the injection of anti-placental
antibody can terminate a pregnancy at any stage, has
stimulated interest in exploring the use of immunologic
methods for population control. Termination of pregnancy
by this means, in species ranging from mice to monkeys,
has had no apparent detrimental effects on the mother or
on fetuses conceived later. Immunization against enzymes
extracted from placental tissue is also being explored.

While immunity to sperm and seminal plasma is fre-
quently regarded as predominantly a problem of the fe-

29

male (i.e. infertility), the increasing use of vasectomy
as a male contraceptive measure has introduced immuno-
logical problems of anti-sperm immunity in males. The
sperm and semen ordinarily do not come in contact with
the immune system of the male since they are normally
confined to the urogenital tract. Following severance of
the vas deferens during vasectomy, sperm may leak into
surrounding tissues. A certain proportion of subjects then
develop sperm tumors (granulomas). These serve as an
effective focus for the induction of an autoimmune re-
sponse in which sperm-agglutinating and sperm-immo-
bilizing antibodies are formed. Further evaluation of
possible consequences of this autosensitization is urgently
needed.

B. Immunology and Development

1. Development of the lymphoid system and deficiencies of
the immune response

As stated earlier, the individual is attuned to respond
to foreign substances but not to self components. To some
extent, this response to antigens is under genetic control.
A number of genes, termed the immune response loci (Ir
loci), which appear to be responsible for the ability to
respond to a wide variety of relatively well-characterized
antigens, have been described in experimental animals.
Evidence is accumulating that similar loci in man ac-
count for the abilities of different individuals to respond
differently to various foreign materials such as ragweed
pollen, a common cause of hay fever. Individuals lacking
the appropriate gene fail to react.

Throughout the fetal, newborn, and young adult stages
of life, the individual undergoes progressive immunologic
maturation. Immune deficiencies caused either by genetic
or environmental factors, or both, may result in abnormal
maturation of the immune system and as a consequence,
undue susceptibility to infection. The division of the im-
mune system into the thymus derived lymphoid cells
(T cells) and the bone marrow derived lymphoid cells (B

30

cells) as described in Chapter 2 has aided immensely our
understanding of these diseases.

Deficiencies of the immune system occur in four large
groups: (1) Primary deficiencies in the T, B, or T plus
B systems are largely errors in normal development.
( 2) Secondary deficiencies may occur because some other
disease, such as leukemia, interferes with the function of
the immune system. (3) Deficiencies arise inadvertently
as a result of treatment with drugs which impair the im-
munologic system. (4) A miscellaneous group includes de-
fects in the complement system and deficiencies found in
the immediate newborn period and in aging. Moreover,
deficiencies in the system of phagocytic cells, especially
of the small phagocytic cells called neutrophil granulocytes,
while not generally included in the immune system proper,
can also lead to increased susceptibility to infection.

Our knowledge of these deficiencies has developed
through the constant interplay between clinical observa-
tion and animal laboratory experiments. Often, new
insights arose through observation and treatment of sick
people. These clinical clues were taken to the labora-
tory where they were analyzed in depth often with the aid
of laboratory animals. The refined knowledge could then
be brought back to the bedside. The severe forms of im-
munodeficiency diseases are rare, but it has now become
apparent that previously unrecognized, less severe forms
of these diseases are widespread.

Primary immunodeficiency may involve nearly com-
plete failure of maturation of both the T and B cell
components of the immune system. Without treatment,
children born with this type of defect invariably die of
infection before the age of two. Recently, new knowledge
of cell transplantation and tissue typing has permitted
complete immunologic reconstitution of some of these in-
fants through transplantation of compatible bone marrow
from a normal subject, usually a close relative. An isolated
deficiency in the T system may occur through absence or
poor development of the thymus. Some such children have
been partially restored by giving them a thymus or a fetal

31

liver transplant; however, these methods of treatment are
still being evaluated. Severe deficiencies in B cell develop-
ment lead to the virtual absence of antibody in serum and
in bodily secretions. Serum antibodies can be replaced by
periodic injections of pooled normal human gamma globu-
lin or by infusion of normal plasma. Thus far, no effective
way has been developed to replace deficient secretory anti-
bodies.

Secondary immunodeficieneies are more common but
are generally less severe than primary immunodeficien-
cies. T and B cells are impaired in various ways in such
diseases as leukemia, multiple myeloma, sarcoid lesions
and in certain viral diseases such as measles. In some of
these conditions, death may come through secondary in—
fection rather than from the underlying disease itself.
Pregnancy also produces profound but temporary altera-
tions in immunologic responses. In addition to using anti-
biotics and to treating the basic disease, ways of boosting
the immune response are being sought.

Inadvertent immunodeficiencies are also common. These
are defects in either or both the T and B systems which are
the unwanted side-effects of treatment with various drugs.
In fact, cortisone, one of the major “miracle drugs,” can
suppress the T system to the point that otherwise rela-
tively harmless organisms such as Candida albicans, a
fungus, can cause invasive disease. There is growing evi-
dence that immunosuppressive and anti-inflammatory
treatment which is now essential for the proper manage-
ment of conditions such as systemic lupus erythematosus
and rheumatoid arthritis, as well as heart and kidney
transplants, may actually cause an increase in the inci-
dence of cancer, due possibly to suppression of the im-
mune surveillance system. Urgently needed and under
investigation are ways to suppress unwanted immuno-
logic mechanisms while leaving beneficial immunologic
defenses unimpaired.

The miscellaneous gronp may be the most common of all.
Ten percent of newborn deaths are caused by infection.
While it is likely that at least one component of the im-

32

SOME FREQUENTLYASKED QUESTIONS AHOUT 044555

What is CASES? OASES is a youth service program started and run by Cal students who
wanted to make a tangible difference in the lives of young children and students through
education, learning, and mentoring. We are a nonprofit organization - active since 1983
- that matches caring adults with children in the 3'd through 12"I grades. We usually have
about 200-250 volunteers each semester.

What type of programs does OASES offer? General Tutorial Monday — Friday; ESL
Assistance on Friday; Kids Into Computers (KICs) on Saturday; and AYPAL, Inspire
Mentorship, which conducts events every other weekend.

How much of a commitment is OASES? We run tutorial Monday through Friday from 4-
6 PM. We also have a Saturday program where kids are taught basic computer skills. if
you do decide to volunteer, we ask that you volunteer once a week on the same day for
the entire semester. Thus, you will see the same student every week and have an
opportunity to build a lasting relationship. Basically, you’ll be committing yourself to
about 3 hours/wk (includes transportation time). There are occasional field trips with the
students and social events for volunteers, which we encourage you to attend.

Where is the tutorial held and how do I get there? The tutorial site is at Lincoln
Elementary school in the Oakland Chinatown area. We will either carpool there or
BART there as a group. If you have a car, we strongly encourage you to volunteer to
drive; you will be reimbursed.

What special skills do I need? Although most of the children are Mandarin and
Cantonese speaking, most of them are fluent enough to interact in English. Thus we do
not have any requirements for language other than English. However, if you do speak
either of these languages, we would definitely be able to use your skills. As far as school
subjects are concerned, we will match you up with the student who needs the most help
in the area that you are most proficient in.

Can I take OASES for units? OASES is available as an Education 97/ i 97 or Asian
American Studies 97/197 class, which may be taken for up to three units (e.g. l unit-1
day/wk, 2 units- 2 days/wk). In addition, some field trips with the students will be
mandatory. Note: you must attend the general meeting on Feb 3 to sign up for units.

How do I know if this is the right program for me? Please come by our table on Sproul
Plaza between to AM-2 PM (table with bright yellow sign). We would be happy to talk
to you further and answer any questions that you may have.

Come to our general meeting on February 3, 2000 6:30-8:00 PM at 2050 VLSB. We’ve
improved our tutorial programl Come find out about our change. Email info®oases.org
for more information or addition questions.

Join O.A.S.E.S. and

tutor children in the

 

Oakland community.

  
   
 
 
   
 

Services,
communi

aboutourp if]
following indi
at 548-1896,
"info@oases.org%o.

htlp. www.oases.org
A Non-Profit Organization

mune system is at fault here, the precise deficit and its
treatment are unsolved problems. Similarly, it has become
apparent that immunological responsiveness wanes slowly
with advanced age. Since the incidence of tumors also
rises ‘with age, it is possible that these two phenomena
are connected; if so, the connection is not yet understood.
This possibility has led to an increasing exploration of
ways to boost the immunologic response, particularly the
T cell system, in efforts to improve anticancer surveil-
lance.

Finally, defects in the granulocyte cells of the blood and
tissues and in the complement system have been shown
to lead to devastating infections. Treatment designed to
boost these defense mechanisms has just begun to be
explored.

2. Embryonic and carcino-embryonic antigens

The surface membrane of the cells of the immune sys-
tem, as well as of all cells in the body, is of a complex, mo-
saic nature. This complexity can best be appreciated
through studies employing immunological detection meth-
ods. The structural configurations so recognized on the
cell membranes are referred to as antigens. The antigenic
surface structure of cells changes between embryonic and
fetal life and again between neonatal and adult life. These
surface antigens may be quite important to growth and
differentiation. Indeed, antigens with tissue-specific de-
terminants arise before the actual structural differentia-
tion of the tissue or organ in the early embryo. Thus, there
is a relationship between the distribution of specific an-
tigens and later embryonic differentiation and develop—
ment. Subsequent tissue differentiation has been ascribed
to interactions between embryonic tissue antigens through
a variety of mechanisms.

The so-called embryonic or fetal antigens often disap-
pear or are masked during postnatal and adult growth.
These antigens are receiving increasing study by im-
munologists at present because it is known that during
certain malignancies, such as leukemia in mice, some of

33

FETUS

 

HEALTHY
ADULT

 
 
   

CANCEROUS
ADULT

 

S URGICAL
REMOVAL

l'

RECURRENCE

 

CARCINUEMBRYUNIC ANTIGEN

Fig. 10. Carcino-embryonic antigen is present in the fetus. Usually
it disappears with development, but is often detected in pa-
tients with cancer of the colon and pancreas. Levels fall follow-
ing surgery but rise again if the tumor recurs. This is depicted
graphically by the bars on the right.

these antigens repressed early in life (for example, the
thymic leukemia [TL] antigen) may reappear. The TL
antigen is present on cells in the thymus but not on other
lymphoid cells except when leukemia develops. The TL
antigen is thus an example of a pre-differentiation antigen
that has been repressed during development only to reap-
pear later, during the malignant transformation of normal
cells. The carcino-embryonic antigen, an early antigen
of the human intestinal tract, is a normal component
of fetal cells and it is also almost completely repressed dur-
ing later development. But it does reappear in malignant
tumors of the intestinal tract. The occurrence of this em-
bryonic antigen in the serum of patients with cancer of
the digestive tract provides not only a possible means for
confirmation of the diagnosis of malignancy, but also a
basis for monitoring the efiectiveness of subsequent surgi-
cal and therapeutic procedures (Fig. 10). Embryonic anti-
gens may also be useful indicators of certain cancers of
the testis, ovary, and liver.

3. I n fectious disease

a. Congenital (prenatal) infection. Although very se-
vere infections in the mother during pregnancy may
threaten the life of the fetus by affecting placental circu-
lation or function, the majority of minor maternal infec-
tions probably have little influence upon the developing
fetus. However, there are a few specific microorganisms
which can invade the maternal blood stream and cross the
placental barrier to infect the fetus. These “congenital”
infections, so called because they are acquired from the
mother before birth, are clinically apparent in the baby
at or soon after birth.

German measles (rubella) and cytomegalic inclusion
disease, both caused by viruses; toxoplasmosis caused by
a protozoan; and congenital syphilis, caused by a spiro-
chete, comprise the four well-studied congenital infec-
tions.

These diseases have certain features in common:
( 1) The mother’s illness, acquired during pregnancy, is

35

often mild and may go unrecognized. (2) The infant’s in-
fection is often severe and generalized. (3) The infection
induces an immunological response in the fetus, apparent
in the form of antibodies of the IgM class. The IgM re-
sponse can be distinguished from IgG antibodies acquired
from the mother by placental transfer. (4) Despite the
humoral immune response of the fetus to infection, in the
case of the viruses of rubella and cytomegalic inclusion
disease, the infected infant may continue to harbor and
shed detectable virus in its secretions for many months.
It thus presents a hazard to other infants or to pregnant
women in the same hospital or institution.

Through the development of tests for specific antibody
in the blood of the prospective mother, the possibility of
congenital infection of the infant can be recognized and
prevented, when effective means of treatment exist. For
example, immunological tests for syphilis are now rou—
tinely carried out before marriage and are an essential
item of prenatal care for expectant mothers. A positive
test before the midpoint of pregnancy can detect maternal
infection before the fetus is involved. The prompt admin-
istration of penicillin to the mother will completely prevent
congenital syphilis in her baby. In the case of rubella, the
goal is two-fold: (1) routine immunization of children
(one to twelve years of age) to prevent epidemics of ru-
bella, thereby reducing the incidence of rubella during
pregnancy and consequently congenital rubella, and (2)
selective immunization of susceptible women of childbear-
ing age.

Although laboratory antibody tests for detection of con—
genital cytomegalic inclusion disease or toxoplasmosis
have been developed, their practical application has not
yet been realized since prevention of these congenital in-
fections during pregnancy is presently not feasible.

b. Neonatal and childhood infection. At birth the infant
with a not-yet-mature immune system is abruptly pre-
sented with a highly antigenic environment. As passively
acquired maternal antibodies (IgG immunoglobulins pas-
sively acquired through the placenta) are degraded and

36

protection decreases during the first six months of life,
the newborn infant is uniquely susceptible to a number of
infectious disease agents. Encounter during birth with a
strain of herpes virus to which the mother is not immune
(hence, the infant’s blood will not contain passively trans-
ferred maternal antibody) may lead to a disseminated
fatal infection in the baby. Likewise, Coxsackie B Virus—
which merely produces fever and malaise in the mother
—may give rise to fatal infection of the heart muscle in the
infant.

From birth on, the infant begins his immunologic edu-
cation, responding to contact with one microorganism
after another as epidemics of various microbial infections
pass through the community. Maturation of the child’s
immune response capacity is not immediate. It proceeds
at a rate and in a way that is not wholly understood. One
goal of preventive medicine has been to enhance the in—
fant’s resistance so that its immunologic education can be
accomplished with a minimum of overt disease.

Classically, this has been accomplished by immuniza—
tion (see Chapter 4) ; the virtual elimination of diph—
theria, whooping cough, and measles by this means has
exerted a profound effect upon mortality in infancy and
childhood. Despite these accomplishments, immunization
has not been successfully brought to bear on many signifi-
cant infectious and parasitic diseases. An example of the
need for further work in developing vaccines is the prob-
lem of bacterial meningitis, which was epidemic in Brazil
and other countries in 1974. Most bacterial meningitis is
caused by three species of bacterial organisms. It has been
estimated that 25,000 cases of H emophilus influenzae
meningitis (the most common form of meningitis in chil-
dren) occur each year in the United States. At the present
time, newly developed vaccines for H emophilus "in fluenzae,
two strains of meningococci, and the more common types
of pneumococci are in various stages of clinical field test—
mg.

Allergic diseases are also of major concern in infancy
and childhood (these are discussed in detail in Chapter 6).

37

Finally, childhood is the setting of a distressingly large
number of neoplasms which may be due to failures of the
body’s immunological surveillance system. Predictably, as
our understanding of the normal immune system’s role in
development increases, areas of disease representing sub-
tle failure of immune function will become more evident.

C. Immunology and Aging

An individual’s antibody response declines markedly
with advancing age (Table I) . His ability to combat acute
and chronic infections is therefore seriously reduced. The
cell-mediated immune system also declines substantially
with advancing age. This system is essential in the recog-
nition of certain types of invasive viruses and fungi; it
also plays a critical role in the recognition of antigens
that appear on malignant cells when they arise within the
body. It is this factor—the weakening of the cell-mediated
immune system—that potentiates the high incidence of
cancer in advanced age. Normally, cancer cells would be
recognized as “non-self” and rejected in the same way that
a foreign tissue graft is rejected. Crippled by the aging
process, the system no longer serves to recognize and re-
ject newly arising cancer cells and this increases our vul-
nerability to death from malignant disease. With

Table 1. Levels of Anti-A and Anti-B antibodies in blood group 0
individuals of different ages. Note the highest levels are found
during adolescence and steadily decline with age. (Thomsen
and Kettel, Z. Immunitatsforsch., 63:67, 1929)

 

 

Age group (Years) Anti—A Anti—B
1/2—1 27 17
1—2 130 69
2—5 287 127
5—10 386 162
10—20 332 139
20—30 291 105
30—40 249 76
40—50 179 53
50—60 174 46
70—80 149 42
80—90 81 28
90—100 38 38

100—102 4, 4, 8, 32 1, 1, 4, 8

 

38

advancing age, not only does the body experience a decline
in both forms of immunity but the immune system also
becomes “perverted,” in that, in addition to failing to react
appropriately to foreign antigens or “non-self,” it reacts
sometimes against “self” or the body’s own tissues. This
perversion is manifested by the appearance of so-called
autoantibodies which react with the individual’s own tis-
sues. Full realization of what these autoimmune attacks
contribute to the degenerative changes of blood vessels
and tissues awaits further exploration (see Chapter 7).

The progressive failure and perversion of the immune
system with advancing age are thought to be responsible
for many of the deteriorative aspects of the aging process.
Without this immune degeneration, many of the “diseases
of aging,” as they are sometimes called, might not occur.
In addition to cancer, these diseases include amyloidosis,
maturity-onset diabetes, and emphysema.

Amyloidosis, while little known to the layman, is a con-
dition that affects practically every person in later life.
Amyloid is a protein-like substance, produced by a dis—
ordered immune system, which accumulates with advanc-
ing age on the connective tissue fibers of nearly every
part of the body, including the brain. Like rust in a com-
plicated machine, it reduces the effectiveness of body
cells. If this unremoved refuse of the immune system
could be prevented, most of us would, no doubt, enjoy an
active and healthier life for a longer period.

Maturity-onset diabetes occurs in a severe form in
about 13 percent of people over the age of 75 and in a
mild form in almost half of the population over 65. It is
well established that some patients become allergic to in-
sulin used to treat diabetes. It is also suggested that the
reaction to insulin and to the cells that produce it con-
stitutes an autoimmune reaction. Prevention of this mal-
function of the immune system would also result in a
longer, healthier lifespan for countless individuals.

Emphysema, one of the most rapidly increasing serious
diseases in the United States and one that is especially
debilitating in old age, is both caused and aggravated, in

39

part, by chronic lung infections. If these infections could
be prevented or controlled by a finely tuned immune sys-
tem, the havoc wrought by emphysema would be greatly
reduced.

Although in ancient times, there was a high death rate
in infancy and early life due to infection, malnutrition,
and other conditions now correctable by modern medical
techniques, then, as now, relatively few individuals lived
on past the age of 90. Aside from death due to discrete
recognizable disease processes, death finally comes from
generalized degeneration of tissue and bodily functions.
Indeed, this process seems to occur at about the same rate
today as it did in the days of ancient Rome. It is believed
by some that failure, breakdown, or dysfunction of one or
another of the components of the immune system repre-
sents the principal mechanism underlying the physiologic
process of aging and that manipulation of the immuno-
logical machinery offers the best possibility for signifi-
cantly retarding the aging process, even if longevity is
not increased.

A number of areas of immunological research look suf-
ficiently promising so that possibly, within the next five
to fifteen years, scientists may be able to modify the actual
processes of aging. One such area of research is asso—
ciated with immunologic rejuvenation. Injection of old
animals with lymphoid cells of young animals of the same
species and strain enables the old animals to withstand
otherwise lethal doses of bacteria. It also greatly dimin-
ishes the anti-self antibody reactions characteristic of old
age. When certain chemicals known as polyribonucleo—
tides are administered to middle-aged mice, they appear
to temporarily rejuvenate their immune systems so that
the middle—aged mice respond like younger animals. It has
also been found that, under certain conditions such as
autoimmune disease, selective suppression of the immune
system may significantly prolong life.

Another area of investigative promise concerns nutri-
tion. It has been known scientifically for many years that
caloric undernutrition in the first portion of life may ac-

40

tually double the lifespan of animals. Indeed this is one
of the most dramatic—and confirmed—experiments of
gerontology. Recent studies suggest that such a diet-
related, marked prolongation of life may operate through
immunological mechanisms. Finally, it is known that body
temperature profoundly affects both the function of the
immune system and the lifespan of certain animals. Sig-
nificance to man must await further studies.

It must be emphasized that this is an area of great un-
certainty because of the limited data available. Relatively
few immunologists have been attracted to these studies,
not because of their lack of importance, but because of
the difficulties involved. One formidable, although appar-
ently trivial, difficulty is in the costly procurement of aged
animals to study. Whereas a young mouse may cost $1.50,
a 2 year old mouse costs in excess of $30, and the figure
may approach $50 during the course of the study. There
is a profound shortage of qualified investigators both in
gerontology and in the borderline areas between immu-
nology, nutrition, and gerontology. Aging experiments
are generally very long term. Therefore, Ph.D. candidates
are unlikely to elect to tackle problems in gerontology for
their theses; hence, few young scientists enter this area,
and a shortage of manpower results. Adequate supportive
training funds might help ameliorate this shortage. The
creation of research and training centers and institutes
which have as their primary goal the advancement of
knowledge in the area of immuno-gerontology should be
undertaken. It is pertinent to note that in 1973 the Federal
government spent about $27,300,000 in socio-medical re-
search on aging, but of this, only about $250,000 were com-
mitted to research on the immunology of aging. This is so
despite the mounting evidence that the immune system
plays a major role, not only in nearly all the diseases of
the aged, but in senescence itself.

In Chapter 9, a number of other ways of stimulating,
suppressing, and otherwise manipulating the immune
system, are discussed. If, through such measures, the im-
mune system can be induced to function normally through

41

one or two more decades of life, then most of us can rea-
sonably expect not only to live that much longer but to
live far more comfortably and productively in our twilight
years.

42

Chapter 4. INFECTIOUS DISEASES AND
POST-INFECTION COMPLICATIONS

In spite of the many “wonder drugs” which are now
available, man is still beset by infectious diseases causing
death, disability, and serious economic loss. Uncontrolled
epidemics of influenza still sweep the country. Pneumonia,
meningitis, many viral diseases of the respiratory and
digestive tract, venereal diseases and many other milder
infections show that infectious disease is still a major
problem even in the most advanced nations (Table II).

It must be emphasized that the most important function
of the immunological system is to protect against infec-
tion. The day to day efficiency of this protection is so great
that it is taken for granted. Only When it is compromised
by failure of proper development, from over-suppression
by drugs, or in some animals by deprivation of maternal

Table II: Some common infectious diseases in the U.S. in 1971

Number of Cases

1971
Gonorrhea 670,268
Strep sore throat and scarlet fever 433,405*
Mumps 124,939
Infectious mononucleosis 100,000 (est)
Syphilis v 95,997
Measles 75,290
Hepatitis Serum 9,556
Infectious 59,606
Rubella 45,086
Tuberculosis (New, Active) 35,035
Salmonellosis (except typhoid) 21,928
Shigellosis (Baeillary Dysentery) 16,143
Aseptic Meningitis 5,176
Rheumatic Fever, Acute 2,793
Amebiasis 2,752
Malaria 2,375
Meningococcal Meningitis 2,262
Poliomyelitis, paralytic 17
1,702,628

‘Does not correct for recurrences in same person, or more than one infection in same person.

Source: Annual Supplanent. Summary 1971. Morbidity and Mortality “Reported Incidence of
Notifiable Diseases in the United States, 1971."

43

colostrom (the antibody-rich milk produced soon after
giving birth), do we see the serious consequences of in-
adequate defense. The child with immunologic deficiency
usually dies after a series of pulmonary infections; the
immunosuppressed patient may die from infections with
viruses, other microorganisms or protozoa. The piglet,
when protected by the antibody in colostrom, can wallow
in the pigpen but will rapidly die from the germs in room
air when kept from suckling. One of the earliest discov-
eries of the immunologist was how to improve the level of
protection through vaccination. Vaccination and immuni-
zation have eliminated or greatly reduced the incidence of
many diseases that were previously dreaded.

This chapter will survey some of the more serious
problems remaining and discuss how they could be
approached by the immunologist.

A. Magnitude of the Problem

It is assumed by many people that antibiotics, such as
penicillin or tetracycline, are adequate to kill all invading
microbes, and consequently that infectious disease is no
longer a pressing health problem. Nothing could be fur-
ther from the truth. Bacteria develop resistance against
antibiotics just as insects, which transmit the great tropi-
cal scourges such as malaria and sleeping sickness, develop
resistance to insecticides. Further, antibiotics are of little
value against most viruses such as those which cause in-
fluenza, rabies, the common cold and a host of others (Ta-
ble III).

Infections are the single largest group of diseases re-
sponsible for illness, represent the most frequent problem
requiring professional attention and account for a large
proportion of the cost of medical care. Approximately 20
percent of all visits to a physician are related to infectious
diseases. The great majority of those visits are for treat—
ment of respiratory difficulties or for kidney or bladder
diseases.

An influenza epidemic in the US. during the Winter of
1968-69 was estimated to cost the American people over
$600 million in direct payments for medical care and

44

drugs, and over $800 million in lost income and produc-
tivity because of absences during the epidemic.

An epidemic of German measles in 1964 and 1965 re-
sulted in the birth of approximately 20,000 children with
serious birth defects. Care for these handicapped children
resulting from a single year’s outbreak of German mea-
sles is estimated to exceed $7 00 million.

During any given year, it is estimated that approxi-
mately 1 million individuals will acquire infections which
will complicate their care and treatment while in hospitals
for other illnesses, resulting in an additional $300 million
in hospital bills. Many such “hospital acquired” infections
are associated with the use of drugs developed in the past
few years to prolong life from leukemia and cancer and to
aid in organ transplantation.

Many of the former major epidemic infections (e.g.
plague, typhoid fever and cholera) have been controlled
in the U.S.A. by improved sewage disposal, vaccination,
and protection of food and water. Most of the infectious
agents which are now important as causes of disease in
man will not be controlled by such traditional public
health measures. These agents include those which cause
respiratory infections, venereal diseases, infectious gastro-
intestinal diseases, hepatitis and infections by antibiotic-
resistant organisms acquired in the hospital and following
trauma. Changing cultural and social patterns in our life-
style have influenced the importance of certain infectious
diseases, such as venereal infections and infections com-
plicating narcotic drug abuse. A variety of apparently
non-infectious diseases such as multiple sclerosis may also
be the result of unrecognized microbial infection. It there-
fore remains critical to advance our knowledge as to how
microorganisms, responsible for these diseases of current
importance, act and how they may be neutralized before
or after invasion of the human body.

B. Principles of Vaccination

The history of a number of diseases proves the effective-
ness of the application of immunology to the prevention
of infectious disease in man. If the human body is exposed

45

917

Table III :

Group

Good vaccine
Effective control
if properly used

Potentially good
vaccine

Fair vaccine
Control inadequate

Experimental vaccines
Field trials in
progress

Available vaccine but
insufficient data to
determine efficacy

No available vaccine
but potential of
developing one

Examples

Smallpox
Polio
Measles
Tetanus
Pertussis
Diphtheria

Rubella
Mumps

Influenza
Cholera
B CG

Pneumococcus
Meningococcus

H. influenzae

M. pneumoniae
parainfluenza
Respiratory syncytial
Pseudomonas

Typhoid
Streptococcus

Hepatitis
Infectious mono-

nucleosis
Syphilis

Problem Areas

Application on continual
basis to all persons at risk.

Long-term protection unknown.

Mutant strains. Partial protec-
tion. Inadequate potency.
Short-lived immunity. Side
reactions.

Duration and degree of protec-
tion unknown. Adverse reactions
not fully defined.

Direct period of protection.
Incomplete protection.

Inability to grow agent satis-
factorily in vitro for vaccine
preparation.

Oncogenic potential. (EBV)

Poor immunogenicity and reinfections.

Immunological control of infectious diseases—status 1972

Needs

Continued clinical and
serologic survelllance and
evaluation.

Continued observations.

Improved potency. Wider
antigenic composition. New
route of administration.
Use of adjuvants.

Field trials.
Surveillance.
Application.

Antigenic composition.
Vaccine development.

Research on vaccine develop-
ment.

L17

'7.

No vaccine available,
current prospects
remote

Gonococcus

Rhinoviruses
Echovn‘uses
Coxsackiewruses

Over 50% of common
acute respiratory
dlseases

Common diarrhea
and acute gastro-
enteritis

Number and types of pathogenic
strains not known.

Too many antigenic types for
practical vaccine use.

Causes poorly understood.

Basic microbiological research.

Common vaccine antigen. Etio-
logic study in the laboratory.

to a killed microbe, to a microbe which has been altered
slightly so it can no longer cause infection, or to certain
microbial products (toxins), the body may make an im—
mune response which will provide an effective defense
against reinfection by the virulent form of the organism.
This is active immunization; the microbial product used
is a vaccine. The success of this type of application of
immunology to the control of infection is perhaps best
exemplified by its use against infantile paralysis, or po-
liomyelitis.

1. Immunization against poliomyelitis

The polio virus enters man through the intestinal tract
where it causes a local infection. The passage of virus
from person to person is greatly facilitated by overcrowd-
ing and poor sanitation. Thus under primitive conditions,
immunity is induced early in life when the infection is
often mild and of little consequence to the infant. As sani-
tation was improved, the chance of infection by direct con-
tact in the environment was lessened, so many people did
not develop early “natural” immunity. Epidemics could
then occur, affecting adults as well as children, causing
great fear and anxiety because of the disabling effects of
the disease.

The polio virus exists in at least three distinct forms of
slightly different chemical structure, each causing a dis-
tinct immune response, and each being susceptible only to
that specific response. Armed with this information, it
was possible to produce immunity to the paralytic form of
the disease by injecting a mixture of killed viruses, called
the Salk vaccine. This vaccine protects the recipient
from the disabling disease but does not prevent multiplica-
tion in the intestinal tract, since local antibody levels are
negligible. Later a modified live virus vaccine was devel-
oped by Sabin that also prevented gastrointestional infec-
tion and gave an immunity that was longer lasting.

The impact of these vaccines on poliomyelitis in the
United States has been dramatic (Fig. 11). Within two
years after the institution of wide-spread use of the killed

48

POLIOMYELITlS
BEFORE AND AFTER VACCINES

 

57.9
40 - - 410 >
U) INACTIVATE‘D Z
O VACCINE U 13
Z >
< ' l r91 :0
‘3 > >
O . -—I l"
I so — I 3.0 g j
I—’ | a
A _ v‘ I
l \ g n
\/ / V a
:3 20 ~ ’ 20 —l rn
U3 / ' :E (n
< o /.\
U C I
— m l
21 > \_,
*5 E
_ 1.0
._ 10 m
I

 

 

 

 

1943

Fig. 11. Total, paralytic and fatal cases of poliomyelitis in the
United States during the 7-year periods preceding and follow-
ing the introduction of the Salk vaccine. (From The Economic
Significance of the Prevention of Paralytic Poliomyelitis,
1955—1961. Updated from the Commission on the Cost of
Medical Care, 3: 29—46, 1964. American Medical Association.)

polio virus vaccine, the incidence of paralytic disease
dropped to one-twelfth of its previous high. With the addi-
tion of oral (Sabin) vaccine, the disease has all but van-
ished in our country. Before the introduction of these
vaccines (1951—1955), over 37,000 cases of poliomyelitis
a year were reported. Following the institution of these
vaccines (1966—1970), only 52 cases on the average were
reported each year. This represents a reduction of almost
1,000-fold in this disabling and frightening infectious dis-
ease. The saving as a result of the utilization of polio
vaccine in terms of direct medical cost and loss of income
is of the order of 2 billion dollars per year.

49

2. Smallpox vaccination

The effectiveness of vaccination against smallpox has
been so profound worldwide that, except in a decreasing
number of endemic focal areas in parts of Asia and Ethi-
opia, the disease has been conquered (Fig. 12). While it
is impossible to calculate the number of lives that would be
lost to smallpox in the United States if the disease were
still endemic, it seems reasonably safe to comment that
urban life as we now know it would be inconceivable in
the absence of an effective vaccine. Because .of the decline
in vaccination in non-endemic areas, smallpox could again
constitute a catastrophic threat if the virus were reintro-
duced. While present surveillance methods are adequate
to exclude infected persons from entering the U.S., a
breach could be effected by illegal immigrants or in the
chaos ensuing from global war.

3. Successful vaccination against other microbial diseases

Other examples of the efficiency of vaccination pro-
grams include measles, rubella, mumps, whooping cough,
tetanus and diphtheria. Measles vaccine (1965) produced
an almost 80 percent reduction in the occurrence of this
disease and its dreaded complication, encephalitis. In one
state alone (California), the vaccine has saved more than
7 million dollars in direct and indirect costs, as well as
preventing the death and permanent disablement of
many. A 50-fold reduction in the incidence of whooping
cough, an important cause of death in young children, has
also been accomplished by vaccination. Tetanus, the fatal
paralysis which may follow deep puncture wounds, has all
but disappeared in the civilian population since the intro-
duction of tetanus toxoid as a generally used vaccine in
the 1930’s. What was a major cause of death of the
wounded in World War I was a trivial danger in World
War II.

The introduction of diphtheria toxoid and its general
acceptance for use in the early 1940’s has caused a 100-
fold decrease in the incidence of clinical diphtheria in
this country since that time. In the first year of complete

50

(New) 171.6! -

 

'5
Ch
‘1

 

r11
-1
D
c.
5‘
:.
5'
:1
"a
9.
a
..
O
a

 

 

 

 

 

 

/ zcao: OHM

 

 

 

Fig. 12. Smallpox endemic countries, 1967 and 1974. (From WHO
Chronicle, V01. 28, No. 8, August 1974.)

51

registration in the United States (1933), there were
50,462 diphtheria cases and 4,937 deaths. With wide-
spread immunization, this dropped to a low of 164 cases
and 18 deaths in 1965. However, a recent outbreak in the
Southwest among non-immunized children indicates the
necessity of continuing public health measures to ensure
adequate utilization of vaccines with proven effectiveness.

The vaccines discussed in this section are effective and
relatively safe. Continued work in this area includes pub-
lic education on the need for vaccination against orga—
nisms which are still potentially threatening, and for
improvements in the safety margin of existing live vac-
cines. It would be desirable to make vaccines only of the
relevant antigenic molecules of the organisms, thus avoid-
ing any possible problems of toxicity and avoiding un-
wanted cross reactivity from using whole organisms; both
are matters for continued research.

4. Infections for which vaccines might shortly be
developed

In addition to these dramatic examples a number of
frequent infections may potentially be controlled by the
applications of appropriate vaccination. These include in-
fluenza, pneumococcal pneumonia, and meningitis due to
the meningococcus (spinal meningitis) or to Hemophilus
influenzae (influenzal meningitis), the latter being an in-
fection commonly seen in the very young. The possible
benefits and some of the problems will be discussed.

a. Influenza. Influenza remains one of the last great
plagues of man. The influenza Virus has the capacity to
change its antigenic makeup periodically and as a result,
human defense mechanisms effective against the virus of
one year may be ineffective for the virus of the next. This
unusual capacity for change is reflected in repeated pan-
demics and annual epidemics. Interestingly, a vaccine
made from killed influenza virus has been employed with
qualified success for over 25 years. However, influenza
continues to be a major infectious disease problem, largely
because of its changing antigenicity. These changes make

52

it difficult to produce a vaccine and obtain official approval ,
for its use between the time a virus change occurs and
the new wave of influenza comes. Fortunately, the number
of antigenic variants appears to be finite and certain
major cycles appear to be established. It thus seems rea-
sonable to attempt to anticipate the type of the next major
epidemic based on previous experience and to stockpile
the appropriate vaccine in advance.

The economic impact of cycles of viral influenza is tre-
mendous. Medicare costs alone during one year (1968—69)
of a pandemic were estimated at over $600 million, to say
nothing of losses resulting from missed work. In addition,
these viral infections of the upper respiratory system can
make the individual more susceptible to bacterial pneu-
monias, or lead to significant illness from other orga-
nisms. In the years 1968 and 1969, a total of 141,857
deaths from influenza and pneumonia were recorded in
the U.S.A. How many people subsequently developed ad-
ditional diseases as a result of the original influenza infec-
tion cannot be determined because of our lack of ability to
make the relevant measurements.

b. Pneumonia and meningitis. The pneumococcus is re-
sponsible for between 200,000 and one million cases of
primary pneumonia a year. Promptly treated by antibi-
otics, the infection is usually controlled within 4 days and
completely resolved in 2—3 weeks. About 5 percent of all
cases fail to respond. Contributing significantly to deaths
and the more serious infections from this organism are
old age or chronic debility from a variety of causes in-
cluding sickle-cell disease, alcoholism, infections of the
middle ear in children, and meningitis in adults. One par-
ticular type of pneumococcus (type III) is particularly
apt to produce complications.

Although this organism is sensitive to drugs such as
penicillin, an effective vaccine would prevent most of the
infections, producing a saving of up to $500 million a
year, and would be especially helpful for the protection
of higher risk individuals. There are several difficulties
in producing a vaccine—the large number of different

53

variants of the organism, each producing a characteristic
carbohydrate (sugar) antigen, and the general difliculties
of immunizing against carbohydrate antigens since im-
munity tends to be short lived. From new knowledge of
basic immunological processes, it should be possible to
manufacture modified vaccines that would induce long-
term immunity against the relatively restricted (15 or so)
types of organism responsible for most pneumococcal in-
fections. Knowledge of ways to immunize against a
carbohydrate antigen would also be of value in the prep-
aration of vaccines against the other organisms, such as
the meningococcus and influenza bacilli, responsible for
most cases of meningitis and of chronic middle ear disease
of children. Meningitis is a particularly distressing dis-
ease. The mortality in children under 5 is between 10
and 20 percent despite appropriate antibiotic treatment.
Of the children who recover from meningitis, between a
third and a half will have permanent disability of the
nervous system and up to 5 percent will require life-long
hospitalization. The cost for medical expenses directly re-
lated to the acute illness alone in meningitis may exceed
50 million dollars a year. The costs of long-term disability
are incalculable. In the case of the meningococcus, vac-
cination of adult and especially military populations with
this material has resulted inprotection against the dis-
ease.

0. Future measures. For control of infectious diseases
discussed above, considerably more research is needed.
Along conventional lines, computer analysis of the known
variations in the antigens of influenza Virus as a function
of time could lead to improved chances of prediction of
future mutations. Increased international surveillance
and cooperation for early detection of a new influenza
Virus strain would allow more time for the preparation of
the appropriate vaccine. For all the diseases discussed,
better knowledge of the antigens, especially as they are
recognized by the child, is required. For a less conventional
approach, methods to alter the antigens, as for example
by conjugating them to various carriers, soluble or non-

54

soluble, to augment the response by the immune system
would be of possible benefit. Most importantly, the po-
tential value of vaccination in these diseases is great,
since they affect the very young and since in spite of our
antibiotic treatment, they continue to kill or maim a large
percentage of the individuals affected.

5. Infections requiring extensive research for
prevention and control

There are numerous infections that afflict a great num-
ber of people and for Which adequate information is not
available. These diseases, therefore, represent an area of
great importance for future research.

a. Ve‘nereal disease. Following the introduction of pen-
icillin, the incidence of the venereal diseases, gonorrhea
and syphilis, fell to negligible levels. With the emergence
of more resistant strains of organisms, widespread ex-
clusive reliance on oral contraceptives, and changing
social values, these diseases are once again endemic (Fig.
13). With both diseases, transmission may occur in the
absence of clinical symptoms.

Untreated, these diseases lead to serious sequelae in-
cluding sterility (most frequently of the female), joint
disease, diseases of the heart and great vessels, insanity,
blindness, congenital malformations and fetal death.
Their economic impact is considerable. Public health mea-
sures by Federal and local governments consume $43 mil-
lion. Direct and indirect medical costs are estimated at an
additional $360 million, of which very little is spent on
research. Future immunologic procedures include more
sensitive diagnostic tests and immunization. The Wasser-
mann test for the detection of syphilis was a triumph of
the early immunologists. While more specific tests are
now also used, reliable procedures for the detection of the
earliest stages of the disease are not available. Pilot tests
for the immunodiagnosis of gonorrhea are promising, but
again no clinical procedures are yet available.

There are no vaccines for these diseases. While the
gonococcus can be cultivated and antigens are being

55

IN THOUSANDS

CASES

650

550

4—50

350

2.5

1.5

GONORRHEA *

 

 

 

 

I I I I I I I I I l l I I I I I I l I I I

 

5O 52 54- 59 58 G0 62. 54’ SC 68 7O

PRIMARY AND SECONDARY SYPHILlS *

 

 

 

 

I I I I I l I J I I I I I I I l I I I I I

 

a) 52 54- 5 6 58 ED 62 64‘ 66 68 7o

HSCAL YEAR
is Reported cases ) UniJced Siaies ,1950 —.’L‘?7.L

Fig. 13.
56

identified, the native organism is not highly immunogenic.
Thus, preparation of effective vaccines will most certainly
present a variety of problems. One approach would be to
present the organism or an antigenic fraction of it at-
tached to a biological carrier. This form of presentation
would result in increased ease of recognition by the im-
munological system. Another is to find better ways of
growing organisms. The organism of syphilis can be
transmitted to animals but cannot yet be readily culti-
vated in the test tube. Large scale cultivation will be re-
quired before a vaccine can be prepared. The urgent need
for production of vaccine for these organisms has been
highlighted by the National Committee on Venereal Dis-
eases.

b. Viral hepatitis. Two forms of the disease are dis-
tinguished. One, virus A or infectious hepatitis, is trans-
mitted orally following the ingestion of infected material,
including shellfish, water and milk. The other, virus B or
serum hepatitis, is typically but not exclusively trans-
mitted through contaminated needles, syringes or blood
products. The viruses of the two conditions are not the
same. Moreover, three different viruses have been isolated
from patients With serum (Virus B) hepatitis. There are
also wide ranges in the severity of the disease. This has
most clearly been brought out where serum hepatitis in—
volves members of a transplant unit. Some such episodes
have involved a series of fatalities, including doctors and
nurses; in others, the form of the disease has been milder,
but may continue to disable for months. Hepatitis is, of
course, a frequent cause of death in drug addicts. The
disease is often present in institutions for retarded chil-
dren. As with poliomyelitis prior to the introduction of
the Salk vaccine, it is difficult to obtain precise informa-
tion as to the number affected annually since many cases
are subclinical.

Recently, a specific antigen (HBAg) has been identi-
fied as associated with hepatitis B, and a Virus-like par-
ticle of unique appearance associated with hepatitis A.
Blood donors are now routinely screened for HBAg and

57

positive individuals are excluded. However, routine tests
of donors for hepatitis A Virus is not yet possible. Another
recent development is the use of immune gamma globulin
in the hope of preventing infectious hepatitis, when a per-
son may be running high exposure risks. Neither proce—
dure is entirely adequate. HBAg antibody cannot always
be detected in the serum of individuals known to carry
hepatitis B virus, and so far immune globulin treatment
has only limited efficacy and applicability.

The virus has been successfully transmitted to lower
primates, thus making studies of the diseaSe process prac-
ticable. Hopefully, techniques will be found to grow the
Virus in tissue culture to enable studies under defined and
controlled conditions and to allow determination of the
number of virus variants. This in turn could lead to meth-
ods to prepare materials for the production of vaccines.
Although success has not yet been reported, past experi—
ence with other viruses suggests that perseverance will
eventually lead to success in development of effective
methods to control and prevent hepatitis.

c. Common cold. While medically of minor consequence,
the common cold causes considerable suffering and severe
economic loss. It is reported that 48 out of 100 persons per
year are affected. This is undoubtedly alow estimate;
other reports suggest rates of 5—6 infections per person
per year. Loss of productivity and medical care are esti-
mated to cost about $2 billion a year. In addition, an enor-
mous sum is spent on cold remedies (e.g. vitamin C) and
symptomatic medication, medication unfortunately often
including antibiotics which have no effects on the virus
but encourage the appearance of resistant bacteria.

No single infectious agent is responsible for the com—
mon cold. Different major categories of virus, including
over 100 different variants of one virus, have been im-
plicated. Development of a vaccine therefore seems un-
likely and research may center on determining why some
individuals remain resistant, how the general and the
local levels of immunity can be increased, and whether
novel approaches such as the colonization of the respira-

58

tory pathways with non—virulent virus could prevent in-
fection with cold viruses.

Since some of the viruses associated with the common
cold and with cold sores of the genitals have been shown
to produce tumors when injected into animals, research in
this area deserves a high priority.

6. The relationship between infection and autoimmunity

Although the usual body response to an infection is the
development of immunity, under certain circumstances
autoimmunity develops, usually as a late complication (see
also Chapter 7).

a. Rheumatic fever and glomerulouephritis. Infections
with virulent (Group A) streptococcal organisms usually
manifest themselves as an acute sore throat, although
some infections may be asymptomatic. A small proportion
of children convalescent from infection, especially those
not treated early with penicillin, develop involvement of
the heart (acute rheumatic fever) or kidney lesions
(acute glomerulonephritis). Either of these diseases may
completely subside or may progress to a chronic state. In
both conditions, body tissues are progressively damaged
by what appears to be an autoimmune reaction. The an-
nual cost of these diseases is conservatively estimated at
$70 million. However, if the costs of heart surgery to re-
pair the damaged valves of rheumatic fever and of dialy-
sis and kidney transplantation are included, the total cost
exceeds $1 billion. The sophisticated nature of the treat-
ment required for these types of diseases is especially
susceptible to inflationary medical costs.

b. Tuberculosis. Primary (pulmonary) tuberculosis is
usually localized to the lung, which is the most frequent
site of infection, and to the lymph nodes draining the in-
fection site. The individual acquires immunity, though
the primary focus may remain infected. Although anti-
biotics cure most patients, they do not save all, and they
may fail to eradicate the infection quiescent in the pri-
mary focus. On subsequent reinfection or on reactivation
of the primary site, tubercles develop which may necrose

59

and cavitate. These lesions have many features of local
immunity, thus accounting for much of the cell damage
seen in this disease. The TB vaccines (BCG) have limited
use in the United States, but have been widely used in
other countries.

7. Unusual infectious diseases

a. Infections common to other countries. A number of
infectious diseases of great worldwide significance are
only local problems within the United States. These in-
clude malaria, leprosy, schistosomiasis, and amoebiosis,
all especially prevalent in the tropics including Central
and South America. While continuing pharmacological
research is increasing the availability of drugs useful in
these diseases, effective vaccines would provide a more
effective means of mass protection of the populations at
risk.

b. Infections of immunologically suppressed persons.
Transplant recipients, leukemia and cancer patients or
those persons with kidney disease or burns, especially
those receiving intensive immunosuppressive therapy or
chemotherapy, may have profound depression of cellular
immunity. These persons are highly susceptible to infec-
tion with yeasts, especially the cryptococcus, certain vi-
ruses, especially the cytomegalovirus, and protozoa such
as pneumocystis. There are no effective preventive mea-
sures for some of these secondary diseases, and thus the
development of vaccines for the induction of specific long-
term immunity before beginning immunosuppressive
therapy could be highly beneficial. While these infections
affect a small minority of the population, their economic
and emotional impact is great. To protect leukemic and
other high risk patients against infection, intensive isola-
tion in complicated isolators called “life islands” is being
increasingly relied upon. The cost of maintaining a single
patient in a life island exceeds $2,000 per week. The dis-
eases included in this section are of great financial impact
to a restricted few. They have a great impact on family
finances and can be ruinous.

60

c. Infection in primary immunodeficiency states.
Although severe immunodeficiency states are rare, condi-
tions in which one or more components of the immunologi-
cal system are depressed are becoming increasingly well
recognized. Respiratory ailments and cutaneous infections
with fungi are common in these immunodeficient people.
Vaccination could have some possible use in certain in-
stances. Transfer factor, a soluble extract of lymphocytes
from known immune donors, has proved of value in other
cases, especially in an immune deficiency disease known
as the Wiscott-Aldrich syndrome.

C. Further Research Needed

Recent studies on transplantation and tumor immunol-
ogy, as in earlier work on immunity to tuberculosis,
have revealed the importance of cellular immunity. Para-
doxically, almost all studies on the efficiency of vaccina-
tion have been monitored in terms of antibody
responsiveness and not on cellular immune reactions.
While both components of immunity, antibody and cellu-
lar responses, are generally evoked by the same stimulus,
these are largely independent responses and one may fade
while the other remains.

In addition, there has been very little research empha-
sis on immunity gained from locally produced immuno-
globulin, although this appears to be extremely important
in preventing or limiting infections of the respiratory,
digestive and reproductive tracts. Local immunity, espe-
cially that due to secretory IgA, may not parallel antibody
levels in the blood and tissue fluids. Thus monitoring be-
comes both more complex and more specific. For agents
entering the bodily orifices, IgA and the lymphoid cells of
the tract of entry would appear to be all important; for
organisms penetrating into the tissues, knowledge of the
comparative levels of specific immunoglobulins and of the
various cellular elements of the immune response will be
required, especially in the development of new and un-
usual vaccines.

61

From these discussions it is evident that we need to
know more about fundamental immunologic processes and
the chemical structure of bacterial and viral antigens.
There is great need for fundamental research on the pro-
cesses of immunity and resistance to infection, and on
ways to manipulate the immunologic system in order to
control and prevent the many infectious diseases which
continue to be problems in this country. In addition, there
is a great demand for persons suitably trained in infec-
tious diseases and immunologic research.

The economic and medical importance of infectious dis-
eases and the real possibility for their control and preven-
tion offer an immense potential for widespread public
benefit. The potential savings in illness and medical ex-
penses warrant a large commitment of funds for re-
search on the immunology of infections.

62

Chapter 5. DIAGNOSTIC IMMUNOLOGY
AND EPIDEMIOLOGY

Most of the chapters in this volume are directed at spe-
cific diseases, what they are, what causes them and what
approaches are being taken to avoid or overcome them.
This chapter is different. It tells how immunological tech-
niques can be used for the detection and monitoring of
abnormalities and diseases. Some of the techniques to be
described are adapted to screening samples from large
segments of the population. Such procedures could be used
for detecting typhoid carriers in a disaster area, or strep-
tococci in the throats of school children. In the future, they
may find wide application in testing for cancer antigens
or antibodies in the bloodstream. Other assays give great
sensitivity to procedures that would otherwise be insensi-
tive, cumbersome or sometimes impracticable. While epi-
demiology and public health seldom make headline news,
they are essential to the general health of the population
and its freedom from epidemics and endemics of disease.
Immunological procedures have found wide application in
this area of medicine and their use is growing rapidly.

Applications of these techniques have been not only in
the expected domains of infectious and immunological
diseases but also to essentially the entire spectrum of
clinical medicine. A previously unavailable armamentar—
ium for measuring drugs, hormones, serum proteins,
tumor and transplantation antigens, and blood group in-
compatibilities impinging on every aspect of medical
practice is now a reality. These methods can be readily
and cheaply applied to large populations. They provide
invaluable epidemiologic and public health tools for assess-
ing both the incidence or predisposition to disease and the
efficacy of immunization programs. They also enable
scientists to uncover major clues leading to a better under-

63

standing of the etiology of disease. Thus, immunologic
methods provide an increasingly important component
of general diagnostic procedures and represent a major
laboratory base for epidemiology and public health.

Documentation of these generalizations is provided in
this chapter through discussion of selected immunological
methods and their practical applications. While the record
of accomplishments is impressive, it is apparent that
serious gaps in our knowledge and technology exist. For-
tunately, these gaps can be filled through research,
training and appropriate support of diagnostic and epi-
demiologic facilities.

A. Measurement of Serum Proteins in Diagnosis and
Management of Disease

There are over a hundred different proteins in human
plasma and each serves a separate, vital function. Mea-
sured immunologically, variation in the concentration of
these plasma proteins occurring in any disease can be
used in making a diagnosis or in following the progress
of a disease or treatment. For example, by measuring the
appropriate proteins, clues can be obtained about the
presence of some kinds of cancer, anemia, kidney or liver
disease, and increased susceptibility to infection. In addi-
tion, it is possible to identify persons at high risk for the
development of diseases of the heart (atherosclerosis),
lungs (emphysema), and central nervous system (Table
IV).

In many respects, our knowledge of plasma protein
changes associated With disease and the application of this
knowledge to medical care is in its infancy. With newer
techniques of rapid measurement, great strides forward
are possible. Moreover, automation has reduced the cost
of materials for such tests to the range of 8 to 30 cents
per sample for each protein.

B. Radioimmunoassays

Radioimmunoassay (RIA) , first developed 15 years ago,

64

Table IV: Some plasma protein deficiency states with clinical

 

abnormalities
Deficient Protein

Albumin Mild tissue swelling (edema)

al—antitrypsin Liver disease, lung“ disease

Transferrin Iron deficiency anemia resistant to treatment

Cholinesterase Sensitivity to certain drugs

IgG, IgM, IgA Increased susceptibility to infection

C3 Increased susceptibility to infection

CS inactivator Increased susceptibility to infection

Clr Increased susceptibility to infection

Ceruloplasmin Liver and central nervous system disease

C1 inhibitor Episodic swellings, including of the airway
(with asphyxiation)

Fibrinogen Mild bleeding tendency

Antithrombin III Tendency to hypercoagulation (thrombosis)

C2 Systemic lupus erythematosus-like clinical pic-
ture (?)

m-antichymotrypsin Allergic symptoms (‘3)

a—lipoprotein Fatty infiltration of liver, spleen and tonsils

B—lipoprotein Gastrointestinal disease; peripheral nerve dys-
function

IgA Hereditary telangiectasis (some patients)

 

provides a general technique for the determination of the
unknown, and frequently otherwise unmeasurable, con—
centration of virtually any compound (Table V). This
measurement is made by comparing the ability of an un—
known material to compete with a known antigen for
antibody. First, the binding of a known antibody to a radio-
active antigen standard is determined. The test is then
repeated in the presence of the unknown sample. The
higher the concentration of antigen in the unknown sam-
ple, the smaller the amount of labeled standard that can
be bound (Fig. 14).

The ability to measure the small amounts of peptide
hormones in plasma by RIA has greatly increased the ac-
curacy of diagnosis of endocrine disorders characterized
by hormonal excess or deficiency. RIA has also resulted in
an information explosion concerning the regulation of
hormone secretion and the interrelationships of hormones
in the body. Moreover, it has led to the discovery of new
hormonal forms in blood and tissues, and has contributed
greatly to our understanding of the mechanisms of hor-
monal release and of hormonal physiology in general.
Novel, striking concepts of the etiology of disease have

65

Table V: Substances measured by radioimmunoassay

Peptide Hormones

PITUITARY HORMONES
Growth hormone
Adrenocorticotropic hormone

(A TH
Melanocyte stimulating hor-
mone (MSH)
a MSH
,8 MSH
Glycoproteins
Thyroid stimulating hormone
TSH

Follicle stimulating hor-
mone (FSH)
Luteinizing hormone (LH)
Prolactin
Lipotropin (LPH)
Vasopressin
Oxytocin
CHORIONIC HORMONES
Human chorionic gonadotropin
(HCG)
Human chorionic somatomam-
motropin (HCS)
PANCREATIC HORMONES
Insulin
Proinsulin
C—Peptide
Glucagon
CALCITROPHIC HORMONES
Parathyroid hormone (PTH)
Calcitonin (CT)
GASTROINTESTINAL
HORMONES
Gastrin
Secretin
Cholecystokinin-pancreozymin
(CCK—PZ)
VASOACTIVE TISSUE
HORMONES
Angiotensins
Bradykinins
HYPOTHALAMIC RELEASING
FACTORS
Thyrotropin releasing factor
(TRF)

Non-Peptidal

Hormones

STEROIDS

Aldosterone
Testosterone
Dihydrotes-
tosterone
Estradiol
Estrone
Estriol
2-Hydroxy-
estrone

PROSTA-

GLANDINS

THYROIDAL

HORMONES

Triiodonthy-
ronine

Thyroxine

Non-Hormonal
Substances

DRUGS
Barbiturates
Digoxin

Digitoxin
Morphine
LSD

CYCLIC
NUCLEOTIDES
CAMP
cGMP
cIMP
cUMP

ENZYMES
Cl Esterase
Fructose 1, 6

Diphosphotase
'IRUS-RELATED
Australia Antigen

(HBAg)

TUMOR ANTIGENS
Carcinoembryonic

antigen
a-Fetoprotein

SERUM PROTEINS
Thyroxin binding

globulin
Rh antibodies
Properdin
I E

g

OTHER
Intrinsic Factor
Rheumatoid Factor
Folic Acid
Neurophysin

been made possible through the precise information given

by RIA.

C. I mmunofluorescent Techniques in the Diagnosis of

Infectious Diseases

Antibodies obtained from blood serum may be chemi-
cally combined With fluorescent dyes. These “fluorescent”
antibodies may be used to detect pathogenic organisms

66

Labelled Insulin Anti —In3ulin Blood Sample

AHJU body
I x + /Ab \ +
Labeiieci Uniabeileé
inguiln —— Antibody :nSuiin — Awtibociy
Camplex Complex
I *— Ab I-Ab

Fig. 14. Radioimmunoassay depends upon competition between
two samples of antigen for the same antibody molecule. The
test can be used for any substance that can function as an
antigen. The figure illustrates the assay of insulin, for
example, in the serum of a diabetic. Other hormones or sub-
stances could be tested for in the same way. A known antigen
preparation is labeled with radioactive isotope. Antibody, the
antigen sample to be assayed, and the labeled antigen are
mixed together. The greater the concentration of antigen in
the unknown, the smaller the amount of labeled antigen that
can combine. Free antigen is washed away and the amount of
label retained is assayed in an isotope counter.

similar or identical to those responsible for their produc-
tion. For example, a physician frequently wishes to deter-
mine if a child’s sore throat is caused by a streptococcus
so that he can prescribe the proper drug to cure the dis-
ease and prevent the serious sequelae of rheumatic fever
and glomerulonephritis. He swabs the child’s throat, cul-
tivates for' a few hours the organisms trapped in the
swab, makes a smear of the cultured specimen on a slide,
stains it with a fluorescent antibody against the strepto-
coccus, and examines the slide under a special microscope
(Fig. 15). If streptococci are present in the culture, they
combine with the antibody and fluoresce brightly whereas
other bacteria remain invisible. This tells the physician
if streptococci are, indeed, present in the child’s throat.
The above test for streptococci has been in use for 15
years and is performed a million or more times each year
in the United States. The procedure is both sensitive and

67

\\\\ /// Fluorescein

Unlabelled /:‘ l
anti 7;, abe led
j Cant Lbodlj

\\ /
' C
Antigen\
Section
8! .defl
u. v light Direct test
\\\\ l ///
-: \H: \\\ l//
\l 1
7

"H

Y‘C
Y'\C
l—SPECI‘RL Antigen
iii—11$ 63%de
Anti thody
Indirect {est Sandwich test

Fig. 15. Immunofluorescence test for both antibodies and antigens.
Antibody (immunoglobulin) is conjugated to a dye (Fluores-
cein) which transmits greenish light when illuminated with
ultraviolet rays. In the direct test, a standard antibody is
labeled and detects antigen in the sample. In the indirect test,
the antibody, which is not labeled, is allowed to react and its
presence is then shown by adding a fluorescent antibody to the
immunoglobulin. The sandwich test is used to reveal the pres-
ence of antibody in a cell. Antigen is allowed to react with the
cell-bound antibody. Fluorescent antibody against the same
antigen is then added and it combines with the bound antigen.
(Modified from Roitt, Ivan M., Essential Immunology, Black-
well, 1974.)

specific. A variant of the test called indirect fluorescence
has been introduced to test for the presence of antibody
in the serum of a patient. Unfortunately, the use of both
tests has been somewhat restricted because of lack of auto-
mation and the high initial cost of the equipment.

Immunofluorescent tests, such as those described above,
furnish valuable assistance in the diagnosis of a large va-
riety of diseases. These diseases include syphilis, infant
diarrhea, gastroenteritis, dysentery, influenza, malaria,
toxoplasmosis, gonorrhea, whooping cough, and meningi-
tis (Table VI).

The general public should obtain all of the health and

68

Table VI: Important diagnostic applications of
fluorescent antibody techniques

Organism Disease
Direct FA Tests
Group A streptococci Streptococcal sore throat and

scarlet fever
Acute rheumatic fever

Rabies virus Rabies
Salmonella Enteric fever and gastroenteritis
Escherichia coli Infant diarrhea
Shigella Shigellosis
Bordetclla pertussis Whooping cough
Hemophilus influenzae 1
Meningococcus Meningitis
Pneumococcus i
Chlamydia trachomatis Trachoma
Hog Cholera virus Hog Cholera
Indirect FA Tests
Treponcma pallidum Syphilis
Toxoplasma gondii Toxoplasmosis
Plasmodia Malaria
Trypanosomes Trypanosomiasis
Leishmania Various forms of leishmaniasis
Trichinella spiralis Trichinosis
Schistosomes Schistosomiasis
Rubella virus Rubella
Cytomeg‘alovirus Generalized disease of newborn
Epstein-Barr virus Infectious mononucleosis
Mycoplasma pneumoniae Atypical pneumonia
Influenza A, respiratory Respiratory

syncytial; adenovirus, etc.

economic benefits arising from the application of these
and similar diagnostic tests. To make maximum use of
these procedures, it will be necessary to further standard—
ize reagents and procedures, develop automated tests, in-
crease the number of trained personnel and continue
research to improve the range, specificity and sensitivity of
the tests and of the reagents.

D. Cell-Mediated Responses in Diagnosis and
Prognosis of Disease

Cell-mediated immunity, Which requires the direct
participation of specifically sensitized lymphocytes and
macrophages, is of major importance in resistance to in-
fection with intracellular organisms, such as those causing
tuberculosis, leprosy, brucellosis or undulant fever, and
possibly even in resistance to cancer. Conversely, cell-

69

mediated immunity can be deleterious, as in the rejection
of organ transplants. Accordingly, diagnostic tests of
varying utility, reliability, and sensitivity have been de-
veloped. These include skin tests and a variety of test-tube
procedures.

The diagnostic importance of skin tests (injection of an
antigen into the layers of the skin) for detecting cell-
mediated immunity is best exemplified in the United
States by the tuberculin test, given to millions of school-
age children across the country. Largely through further
diagnostic evaluation and treatment of children identified
as having positive skin tests, the incidence and spread of
tuberculosis in the United States has been drastically
curtailed.

However, skin tests for cell-mediated immunity may
occasionally be ambiguous and it may sometimes be un-
wise to challenge the patient with the specific antigen.
For example, introduction of transplantation antigens
might immunize a patient and accelerate rejection of an
organ transplant. For these reasons, emphasis has been
placed on a variety of test tube (in vitro) procedures for
evaluating cell—mediated immunity. These include specific
and non-specific tests of lymphocyte function which are
based on the degree of stimulation of blood lymphocytes
when mixed with antigen or with general lymphocyte
stimulants. This type of test is being employed in detect-
ing an increasing variety of diseases.

Perhaps the most important contribution that the study
of cell-mediated immunity could make would be in im-
proved diagnosis and therapy of cancer. In some human
studies, survival after surgical removal of solid tumors
seems to depend in very large part on the degree of cell-
mediated immune responsiveness of the patient. Tests have
been developed by which the lymphocytes of cancer pa-
tients can be tested for their ability to destroy either their
own or other tumor cells of the same type in vitro. At
present these tests are difficult and capricious, although
rapid progress is being made in animal studies. As more
is understood about their basic mechanisms and more in-

70

formation accumulates on their predictive value, these
tests should be increasingly important in providing an in-
dex 0f the patient’s ability to effect his own cure, and the
extent to which tumor therapy and radiation will contrib-
ute to or compromise that ability.

E. Immunohematology and Blood Banking

Basic immunological research has had major influences
on immunohematology. It has helped provide a broad array
of essential new diagnostic reagents and this in turn has
minimized the risk of blood transfusions. Under normal
circumstances, patients are typed for their A, B, O, and
RhD antigens through direct agglutination of their red
cells by antisera that react with the A, the B, or the Rh
antigens (Fig. 16). Prospective donor blood of the pa-
tient’s type is then “cross-matched” with patient serum, a
technique which involves incubation of donor red blood
cells with the serum of the patient. Agglutination indicates
that antibodies present in the patient’s serum react with
cells from the potential blood donor. When such antibodies
are present, their type can be determined and a special
blood donor selected. The ability to detect preexisting anti-
bodies has helped prevent potentially fatal transfusion
reactions. In addition, knowledge of immune lysis and
complement fixation now rests on a solid biochemical
framework.

In addition to providing important diagnostic reagents,
basic immunological research has provided the information
which has made the development of therapeutic reagents
possible. The understanding of antigen—antibody reactions
and of their kinetics resulted in the development of Rh
immunoglobulin. The use of anti-Rh antibody of high
affinity has virtually eliminated the fairly common and
serious disease, Rh erythroblastosis, of newborns.

Despite improvements in patient therapy and practical
applications in disease prevention made possible by
basic immunological research, many important and prac-
tical problems remain to be solved. One very common prob-

71

C(umpin or A [DELnation
0‘? Red Blood CBHS Tgpe A
b5 AnJcL - A An£Lbod5

NO Aag\ujcihachon
0‘»: Red Blood Cell Tgpe, 8
b5 A n+1 —A A nfL beds

ABO TYPING

Fig. 16. Modified from Zmijewski, Chester M. and Fletcher, June

L., Immunohematology, Appleton-Century-Crofts, 1968.

72

lem relates to management of the patient with leukemia
or with failure (aplasia) of the bone marrow. Both types
of patients are prone to spontaneous bleeding due to
inadequate production of platelets by the bone marrow.
Some cures in aplastic patients have followed the admin-
istration of bone marrow from a normal donor (see Chap-
ter 8). In both types of disease, benefit has also resulted
from platelet transfusion. However, after the repeated
transfusions necessary to maintain patients with bone
marrow failure, antibodies often develop which result in
rapid destruction of transfused platelets. This reduces the
benefit of subsequent platelet transfusions. Attempts to
characterize antigens which play a major role in the im-
mune response to platelet transfusions are under way,
and some transfusion centers are exploring the practical-
ity of using tissue typed donors (see Chapter 8).

' Further understanding of antigen—antibody reactions
and continuing identification of antigenic complexes which
play an important role in transfusion of blood or blood
products, are required. Only through basic research in
these areas, followed by practical application in transfu-
sion therapy, will immunohematology continue to develop
new and truly effective biomedical services.

F. Tissue Typing

The importance of information about tissue antigens is
becoming increasingly apparent since the reaction against
these antigens causes graft rejection. Tissue antigens are
analogous to red cell antigens but are found on the sur-
faces of lymphocytes and body cells rather than only on
the red cell. At first almost exclusively restricted to the
selection of kidney donors, tissue typing is being increas-
ingly used to avoid transfusion reactions to whole blood,
platelet, and White cell transfusions. Knowledge of the
tissue antigens of donor and of recipient is also essen-
tial for bone marrow replacement in the treatment of leu-
kemia, in many forms of cancer, and in immunodeficiency
diseases. In addition, people of certain tissue types may be
more susceptible to some specific diseases.

73

The most important, widely occurring, and easily de-
tected cell surface antigens today are the HLA antigens.
Modern knowledge of HLA tissue antigens dates back to
about 1960, at which time three HLA antigens had been
described on white blood cells. Now, about 60 HLA vari-
ants are known and there are clear indications that the
list is incomplete. The HLA antigens are found on
lymphocytes, platelets, and nearly all tissues and organs.
Although “tissue typing” can mean determination of any
number of a tremendous array of cell surface antigens, it
most commonly refers to “HLA typing.”

The tissue typing or HLA typing procedure is based
upon the ability of antiserum (containing the antibody)
to lyse lymphocytes (carrying the antigens) in the pres-
ence of complement. Since some of the antigens are not
well characterized, a very large number of antisera must
be used for HLA typing, and automation is not generally
possible. Furthermore, the number of qualified tissue typ-
ing laboratories is small, only a few people can be tissue
typed by a laboratory in one day, and the cost of each
typing is high.

While progress in this area is rapid, much remains to
be accomplished. Urgently needed is an exact analysis of
the antigens so that they can be synthesized and used for
the production, in animals, of HLA typing antisera, and
for the induction of unresponsiveness to transplants in
man. Also needed is an assessment of the biologic impor—
tance of each of the antigens as some are probably more
critical than others. Typing for transplantation of organs
or of bone marrow would be greatly simplified if typing
could be restricted to the most potent factors. Knowledge
of the HLA antigens is already of value in diagnosis;
for example, in helping the physician decide if a young
person is liable to develop the spinal deformity ankylosing
spondylitis. This type of predictability may also be ap-
plicable to certain types of cancer, allergies, and other
diseases.

74

G. Diagnosis and Epidemiology of Parasitic Diseases

Although infestation with major pathogenic parasites
is uncommon in the U.S.A., parasitic diseases remain
a serious problem in most tropical areas of the world.
In this country trichomonas vaginalis is one of the most
frequent venereal diseases, pinworm is common among
children, and both cause a certain morbidity, especially in
the underprivileged. Simplified mass screening procedures
would be extremely advantageous.

Traditionally, the parasitologist has relied upon mi-
croscopic observation for the detection and identification
of parasites. Recently, however, immunodiagnostic meth-
ods are becoming increasingly important in those cases
in which the parasites cannot be detected readily by mi-
croscopy. Procedures most frequently employed for the
immunodiagnosis of parasitic diseases include comple-
ment fixation, indirect blood agglutination, immunofluo-
rescent procedures using whole organisms or soluble
antigens prepared from them, flocculation tests and
hypersensitivity reactions.

New immunodiagnostic methods could also be used to
determine Whether transmission of infection in endemic
areas has been interrupted by control measures. It is well
established that the specificity and sensitivity of immuno-
diagnostic procedures depend on the quality of the antigens
employed. The introduction of better methods for isolat-
ing the active antigenic components from crude parasite
extracts has significantly increased the value of many
immunodiagnostic tests. Since the chemical nature of the
major specific antigens difiers among the various para-
sites, no single method is universally suitable for antigen
fractionation and purification. _

In addition, problems often arise because of the wide
variety of procedures used in different diagnostic labora-
tories. There is an urgent need for improvement and
standardization of antigens and of assay techniques. The
study of immunotherapy in parasitic diseases, such as
development of vaccines, is in its early infancy. However,

75

early results of a few studies on malaria, and on intestinal
parasites of grazing animals, encourage pursuit of this
line of research.

H. Serological Epidemiology and Public Health

The analysis of blood samples, taken from a representa-
tive sample of a population, for antibody to various infec-
tious agents is called serologic epidemiology.

Application of such methods by the World Health Or-
ganization has provided evidence of the presence and
distribution of infectious agents such as arboviruses, influ-
enza, poliomyelitis, malaria, and other parasitic diseases
in countries and settings where medical, diagnostic, and
public health facilities are often inadequate to recognize
and report such conditions. In other cases, the use of this
technique has revealed which people need tetanus, diph-
theria, whooping cough, rubella, and other immunizations.
Properly used, it is possible to reveal evidence of both cur-
rent and past infections, and both clinical and subclinical
infections. This type of information could be obtained in
no other way. By serial sampling of a group of people
over a period of time, the incidence of infection can be
ascertained between each sampling period. Epidemiologic
techniques have their most important applications in de—
termining the need for vaccination and the quality and
duration of protection afforded after immunization. In re-
search laboratories, seroepidemiological studies have re—
sulted in the association of Australia antigen with serum
hepatitis, and of Epstein-Barr virus With infectious
mononucleosis. From such research have come the vital
screening programs to minimize the risk of hepatitis
following blood transfusions. The future holds great po-
tential in prospective studies for cancer antigens, for im-
mune deficiency diseases, for evaluation of new vaccines,
and for identification of the diseases associated with
newly discovered infectious agents.

76

I. Immunology as Applied to Forensic Medicine

An area of great potential application of immunodiag-
nostic procedures lies in the identification and quantita—
tive determination of narcotic and hallucinogenic, agents,
including morphine and cannabis derivatives. Screening
techniques comparable in simplicity to those now used for
estimating breath alcohol can be projected for law enforce-
ment purposes. The sensitivity of immunologic assays can
also aid in determining tissue drug levels for investiga-
tional purposes. Thus, collaboration between law enforce-
ment agencies and immunologists should be established
as a matter of urgency.

The precipitin reaction and other serodiagnostic pro-
cedures can be used to identify the sources of blood and
seminal stains. Blood grouping procedures have been
adapted to provide additional information about the indi-
vidual source. In the case of fresh tissues, tissue culture
can be adapted to permit determination of the tissue an-
tigenic type. Determination of red cell, leucocyte and
serum antigens can give increasing precision to determina-
tion of paternity, almost to the point of giving positive
identification, rather than paternity exclusion as in the
past.

J. Conclusions

It may be confidently predicted that the broad impact
of immunology on diagnosis, patient care and public health
will continue into the future and will prove to have been
only an opening wedge into the medical armamentarium
of the future. The impressive accomplishments attained
so far give clear insights into unmet challenges, poten—
tials, and needs which, if realized, could very significantly
improve and expand direct services to individual patients
and to population groups. The experience of WHO with
smallpox shows that it is possible to eradicate completely
this disease from whole continents. Eradication of other
diseases such as tuberculosis, cholera, typhoid, and even

77

influenza is conceivable, but only with the aid of mass
screening procedures, such as those discussed in this
chapter.

78

Chapter 6. ALLERGY AND DRUG
REACTIONS

As has been recognized in previous chapters, the immune
system is not infallible. It can malfunction and result in
autoimmune disease, or it can over-react following contact
with otherwise harmless foreign substances and cause al-
lergic disease. Four major classes of malfunction, in addi-
tion to the autoimmune or autoaggressive reactions
discussed in Chapter 7, are recognized: Class I: Immediate
Anaphylaetic Hypersensitivity; Class II: Cytotoxic Reac-
tivity; Class III: Immune Complex or Aggregate Type;
and Class IV: Delayed Hypersensitivity.

Immediate anaphylaotio hypersensitivity, Class I, exem-
plified by hay fever, asthma or allergicm sudden death, is
manifested within minutes after a second exposure to the
offending antigen (or allemen). Subjects showing this
immediate allergic response are called atopic and their
hyperresponsive state, atopy (Fig. 17 ). Only recently has
it been shown that these atopic reactions are due to the
activities of a special class of antibody, sometime, lled
reaginic antibody or r in, and now known to bۤ1n
atopic individuals, thgmbination of IgE antib with
allergen on a mast cel a particular type of granulocytic
cell found in tissues, results in the release of mediator
substances from the mast cell. These mediators, primarily
W and slow reacting substance, w, cause the
blood vessels to swell and leak fluid, stimulate the sensory
nerves to cause itching, sneezmg or coughmg, and contract
the “muscles of the bronchialfitree, cau g obstruction of
the flow of air in and out of the lungs ( ig. 18).

Cytotoxic reactivity, Class II, is also an immediate re-
sponse, and involves a harmful immune response against
the antigens of cells such as red blood cells. It 1s typified
by the response in an incompatible blood transfusion,

79

 

Fig. .17. Cutaneous anaphylaxis (wheal-and-erythema response)
in man. Fifteen minutes before the photograph was taken the
subject was injected intradermally with 0.1 ,ug protein ex-
tracted from guinea pig hair. Note the irregularly shaped
wheal. The surrounding redness or erythema is not easily vis-
ible in the photograph. N 0 reaction is seen at the control site
where 0.02 ml of buffer alone was injected. (From Davis, B. D.
et al., M ierobiology, Harper and Row, 1973, reprinted with
permission.)

Where there is vague general discomfort before the blood
transfusion is complete. This is followed by pain, air
hunger, a sense of chest constriction, then rapid heart
beat, falling blood pressure and even shock in severe cases.
In Class 11 responses, the rapid destruction of foreign, in—
compatible red blood cells is due to an IgG antibody in the
plasma of the recipient.

Immune complex disease or aggregate amphylaxis,
Class III, as seen in the hives of serum sickness, occurs
Within several hours and results from a combination of
IgG antibodies and antigen. As large aggregates of IgG-
allergen form, the immune complexes are deposited in the
walls of bloodvessels or in the kidney, and the complement

80

  

A Allergen

Ani: ibocly (13 E)

Fig. 18. Respiratory and Food Allergies. Antibody (IgE) at-
tached to the surface of mast cells near the capillary blood
vessels binds allergen as it enters the body. The act of com-
bination leads to release of histamine and other chemical
mediators. Common sites of reaction are (A) the gastro-
intestinal tract (diarrhea and vomiting) ; (B) the nasal pas-
sages (hay fever) and (C) the lungs (asthma).

system is activated. In this form of anaphylaxis, as in
Class 1, some of the effects are due to the release of hista-
mine. The method of release, however, is different. In
> Class III, the fixation of complement leads to the forma-
directly with the mast cells andrelease histamine. Also as
a result of complement activation, another granulocytic
cell called a neutrophil is stimulated to engulf the com-
plexes. Unfortunately, this process damages the neutro-
phils and they, in turn, release additional (lysozomal)
enzymes that damage the surrounding tissues.

81

Delayed or Class IV hypersensitivity begins after a la-
tent period of several hours and reaches a peak at 48 to
72 hours. This allergic malfunction is dependent” on the
activity of lymphoid cells rather than antibody. When the
allergen or antigen reacts with specific recognitionsites
on the surface of lymphocytes, a series of interactions ac—
tivates the lymphocyte to secrete a number of factors
(lymphokines) which alter the function of. other- cells.

is response is an important part of the process of graft
rejection, tumor immunity, and immunity to many infec—
tious agents, especially those producing chronic diseases
such as tuberculosis.

This chapter considers the prominent allergic and drug
reactions—what they are, Why they happen, and what can
be done about them.

A. Immediate Anaphylactic (Class I) Hypersensitivity
l. Allergic sudden death (anaphylaxis)

This is one of the manifestations of immediate anaphy-
lactic hypersensitivity and may occur after insect stings
and after certain medications, especially those given by
injection. Similar, but less severe reactions may occur from
certain foods. These diseases are quite common and while
their exact incidence is unknown, it is likely that several
thousand deaths a year occur in young people which could
be prevented.

In each case a sensitizing experience with the allergen
material (such as penicillin) hastakmplacgpreyiously
and probably without noticeable reaction. This ,,pr' '
experience incites t Wendeyelopment of immunoglobulin E
(IgE) antlbndmswhmhsflxlm 019mm Mast); cells.
On the sWWithith the same a1-
Lergen, the combination of thaaflergen with mast cell
bound antibodies causes release of chemical mediators

 

which act vents that r ' as-
phyxlamwmsy s (see Figure

18). In severe cases, Without medical intervention, death
can occur within half an hour.

82

2. Allergic rhinitis (hay fever)

Allergic rhinitis is commonly seasonal, occurring when
certain pollens and fungal spores are abundant. Nonsea-
sonal forms due to animal danders, dust and molds, etc.
are also well known. Hay fever affects nearly one Ameri-
can in ten, and occasions 9,000,000 to 15,000,000 Visits to
physicians annually. It rivals the common cold as a reason
for purchase of over-the-counter remedies.

The disease is mainly one of adult life which affects the
nWes. Affected individuals are often
prone to other atopic conditions, including asthma and
hypersensitivity to aspirin. Once an individual has be-
come sensitizgdwh§_,t§.n_d.§,_to.-become reactive to ,other-,a.ller-
gens. Genetic factors are strongly involved in the genesis
of allergy. One of the genes responsible for the allergic
reaction to ragweed appears to be linked to the major
histocompatibility system HLA (see Chapter 5). Many
allergens capable of inducing allergic rhinitis have been
identified and some have been extensively purified.

3. Asthma

This is the term used for a variety of conditions, the
common factor being constriction of the lower airways of
the lung. The underlying cause is an increasedmspgnsive—
ness of wtheJungs to. agentssnchasbstamme. The small
blood vessels of the lung contain manym mast cells which,
when stimulated by antibpdy-antigen 1nteract10ns Lelease
their whistarnine, thus inducing contraction of the smooth
muscle surroundmg the smmays. Asthma maybe
triggered by exposure to dusts or pollens, in which case it
may co- exist with allergic rhinitis. Childhood asthma is
usually preceded by atopic dermatitis and frequently dis-
appears at puberty. Another form of asthma, infective
asthma, often develops in adults over the age of 40, and is
commonly associated with sinusitis or chronic bronchitis.
Allergy to aspirin sometimes manifests itself as asthma,
while yet another type develops in women during the early
stages of pregnancy.

It is estimated that four percent of Americans currently

83

have asthma, and that another three percent have had
asthma attacks at some time in their lives. The childhood
form can interfere with both physical and mental growth.
Asthma is a most distressing disease since attacks begin
without warning, thus sufferers can never be confident
about going to work or school because of the unpredictable
nature of their condition. A minority of patients remain
almost continuously disabled. In a single year, asthma ac—
counts for 85 million days of restricted activity, 33 mil-
lion days in bed, and 5 million days lost from work. The
hospital costs for asthma patients exceed $86 million
yearly.

Since asthma is not a single disease, but a family of
diseases with a common symptom, the results of skin tests
with allergens differ. Patients with juvenile asthma usu-
ally give positive skin tests while patients with infectious
asthma may not. In highly sensitive patients, conventional
skin testing may actually provoke an asthmatic attack.

4. Ato pic eczema

This is a condition affecting young children which usu-
ally persists until puberty. It is characterized by itching
and a skin rash which affects especially the skin in the
flextures of the elbows and knees, although much of the
body may be affected. It does not follow a constant course
and is liable to sudden flare-ups preceded by intense irri-
tation, often at times of emotional tension. The associa-
tion between mental state and atopic eczema or asthma
has long been noted, but the basis is not understood.

Genetic factors predispose to atopic eczema, since the
disease tends to “run in the family.” Nevertheless, no sim-
ple mode of inheritance has been found from family or
twin studies, and several different genes may be involved.

Affected patients have abnormally high levels of IgE,
the antibody class implicated in other atopic conditions.
The inciting antigen is unknown and the disease has some
attributes of autoimmunity. Eczema, like asthma, re-
sponds well to treatment with corticosteroids. However,
the steroids are powerful agents with dangerous side ef-

84

fects. If the nature of the inciting agent and the mecha-
nisms of the reaction were known, less hazardous methods
of treatment could be attempted. Such answers will be
found in further research.

5. Treatment

All forms of immediate anaphylactic hypersensitivity
respond well to steriod hormones such as cortisone. There
are, however, vefirious drawbacks to the prolonged use
of these powerful agents and a rich variety of other drugs
may be employed. Antihistamines are effective in a few
of the allergies but not in others, including asthma. New
drugs are constantly being introduced; in general they
only partially alleviate the symptoms and introduce unde-
sirable side effects as every sufferer from hay fever knows
from experience. Further, drug treatment is directed
against the symptom and not against the cause.

There are two conventional immunologic approaches
and a variety of new and interesting ones. The conven-
tional approaches are avoidance and desensitization.
Avoidance is entirely effective, and many people have
found it desirable or necessary to change their place of
residence or their occupation, or to give up their pets to
escape exposure to a specific allergen.

Desensitization, or more correctly, hXPQ§£E§ltléfl§lle is
one of’the'oldest forms of treatment of any immunological
disorder. Unfortunately, it was found to be effective be-
fore modern practices had been developed, and dosages
were worked out in an uncontrolled and empirical manner.
The vaccines made from pollens, dusts and other agents
were not standardized. Little scientific knowledge was
gained from years of experience, and only recently have
serious attempts been made to isolate, purify and stan-
dardize the materials used for desensitization. When puri-
fied antigens have been used in a controlled manner,
valuable information has been obtained. The common a1-
lergen, ragweed pollen, has been fractionated and purified
antigens prepared. One such subunit of ragweed antigen
(called Ra5) has been chemically characterized and found

85

to contain 42 amino acids. Through the use of these puri-
fied antigens, it has been found that immunization induces
a rise in the level of specific IgG and a dramatic and often
sustained fall in the level of the corresponding specific
IgE.

It has also been discovered that the combination of the
allergen with immunoglobulin E (IgE) antibodies fixed
to target body tissue cells initiates a complex sequence of
events which lead to the release of the chemical mediators
of the allergic reaction. These mediators are numerous
and varied, and include histamine and prostaglandins.
The release of these mediators is influenced by an enzyme,
adenyl cyclase, which affects an energy transfer system of
the lymphocyte, through an intermediate substance called
cyclic AMP. High levels of cyclic AMP generally decrease
secretion of allergic mediators. A better understanding of
the actions and interactions involved promises to lead to
new methods of therapeutic intervention, and to new ap—
proaches for blocking the allergic process at various se-
lected points. Research studies aimed at such intervention
are uncovering the effective action of currently used
drugs and are leading to the discovery of additional useful
drugs. Most significantly, while it has long been suspected
that the nervous system has a frequent role in the broncho-
spasms of asthma, the nature of the relationship has been
unknown. The newer information now becoming available
should, for example, help us to understand why nature’s
own muscle relaxant, the hormone epinephrine, is rela-
tively ineffective, and why histamine is so potent in
asthmatics.

Another area where the availability of purified re-
agents is expected to be of great value is in skin testing,
and the evolution of new assays for hypersensitivity, a
realm in Which precise information is urgently needed
(Fig. 19). Present skin tests often fail to indicate which
of a variety of agents is actually responsible for the dis-
ease because of the complex nature of the antigen being
used. A patient sensitive to elm pollen, for example will
often cross react with many other pollens as well, and

86

only by prolonged observation is the culprit allergen
identified. In some cases, the true allergen may be a break-
down product rather than the whole material.

Radioimmune assay is the ultimate test. It will be able
to give precise quantitative measurements of the level of
IgE to specific antigens present in the serum. It now ap-
pears that certain allergic reactions may result from high
levels of antibody in isolated tissues and that tissue anti—
body levels might not be reflected by skin testing or even
by serum antibody levels. This complication emphasizes
the need for a new technology for accurately defining an-
tigen hypersensitivities affecting specific target organs in
atopic individuals.

B. Serum Sickness and Hives

Segrumwsigkness occurred frequently before the antibi-
otic era, when specific antisera produced in horses or rab-
bits were commonly used in treating human infections
such as diphtheria, tetanus, pneumonia and meningitis.
It still occurs (When animal serum must be injected into
humans for the prevention of rabies, or for the treatment
of snake bites or gas gangrene} It can also follow the ad-
ministration of certain drugs. As serum therapy is seldom
required in modern medicine, drugs—especially penicillin
——are the most frequent cause of serum sickness today.

Some 7112 days after injection of the serum or‘drug, a
particular type of immune reaction occurs in which the
patient .d. eyelppsswollen.painiuliointsaferersanihiyesor
othwskinxashes. In severe cases, there may be damage
to the small arteries of the heart, kidneys and nerves. Mild
cases can be treat§fl_,.With, aspirin.and..,.,anti.hi§§§miees-
Severe cases require corticosteroids. A recent report claims
that antihistamines given regularly after the injection of
the foreign serum may prevent serum sickness. This opens
a promising lead for clinical investigation of the treatment
of this and similar diseases. Development of a reliable
means for preventing serum sickness would allow freer
use of some important drugs which, currently, cannot be

87

88

     
   

N .7)

NEGATIVE
INTERMEDIATE
sTRONG POSITIVE

$

$ SKIN TEST

 

NMW/WM

&

68

Fig. 19. , In skin testing a variety of allergens are injected into
the skin in an orderly sequence. Some allergens elicit a local
inflammatory response.

used in some patients because of the threat of this reac-
tion.

While Hives is a prominent symptom, both in serum
sickness and in anaphylaxis, it commonly occurs as an iso—
lated symptom. As many as 20 percent of the population
consult a physician for hives at some time in their lives,
While nearly everyone has minor isolated episodes. Hives
can be produced by allergy to foods, food additives such as
saccharin, tartrazine (butter yellow) and sodium benzo—
ate, as well as by drugs and infectious agents. Other com-
mon causes include physical stimuli such as cold, heat,
light, vibration, and pressure. Many, if not most, chronic
cases have no identifiable cause and they remain a dis-
tressing problem.

A particularly severe form of a related allergic condi-
tion, hereditary angioedema, is fatal in up to 25 percent
of the affected patients. When such attacks involve the
larynx, the patient can die of asphyxiation. Recent inves-
tigations have identified the exact nature 'of the inherited
defect, a dominant gene which causes a deficiency of a
normally present inhibitor of the activated first compo-
nent of complement (Cl esterase). Partial success has
resulted in the identification of an enzyme inhibitor,
epsilon-aminocaproic acid, which will prevent attacks, but
very large doses of this drug are required. More effective
derivatives are being sought in current research.

C. Hypersensitivity Pneumonitis

Hypersensitivity pneumonitis is a diffuse disease of the
.It appears to be caused by a com-

plex allergic reaction to organic dust particles small
enough to penetrate to the most distant parts of the air-
way. While the immunopathologic mechanisms of this
condition are not yet fully understood, those persons af-
fected have large amounts of IgG antibody reactive with
organic dusts, and the injury to the lung has been consid—
ered to be of the “serum sickness” type. The processes re-

90

sponsible are not simple and there is strong evidence that
the mechanism of the injury includes delayed hypersensi-
tivity.

The chief precipitating causes are spores of molds
which grow at high temperatures in rotting hay and other
vegetable material. Similar organisms grow in some hu-
midifiers and air conditioners and can be a serious and
often unrecognized hazard. Other causes are vegetable fi-
bers and excreta from birds, especially pigeons and para-
keets. Occupational outbreaks of farmer’s lung, pigeon
breeder’s disease, bagassosis and byssinosis (diseases
caused by inhalation of dusts from sugarcane and cotton)
are all well described in the scientific literature. Interest-
ingly, “diseases of sifters and measurers of grain” were
described as early as 1713.

Repeated temporary disability rather than mortality is
the major problem of these diseases. Acutely ill patients
usually recover within several weeks. Recovery is complete
and permanent if exposure ceases. With continued expo-
sure, however, extensive scarring of the lungs develops
and patients become permanently disabled by extreme
shortness of breath. Many of these patients ultimately die
of this complication.

D. Contact Dermatitis

Contact dermatitis is a form of delayedhypersensitiv-
ity in which the maior target cells an: in tha skin. The
most common causes in the US. are poison ivy and poison
oak. Other common sensitizers are metals, chemicals in
rubber, and medications (neomycin, penicillin, deter-
gents, and local anesthetics) (Fig. 20).

Contact dermatitis 1s a common cause of time lost from
work. Between one-half and three-fourths of occupational
disease in this country is due to skin disorders, mostly
contact dermatitis. The condition can be recognized by the
rough scaly appearance of the eXp0§ed Skin. The offend-
ing allérgen can often be identified by skin testing. While
not every individual exposed Will become sensitized, there

 

91

 

Fig. 20. Nickel dermatitis. Area of irritation corresponds with the
contact area of the back and metal band of a wrist watch (C) .
Mercury dermatitis. Patient is sensitive to mercuric sulfide
(Cinnabar) in his tattoo (D). (From Humphrey, J. and White,
Immunology for Students of Medicine, Blackwell, 1970,
courtesy of Dr. J. A. Milne, reprinted with permission.)

is no practical way of predicting who among prospective
employees Will be vulnerable to this allergy or when they
Will become affected. Recent animal studies suggest that
genetic factors may influence individual susceptibility.

92

There is no effective treatment other than avoiding con-
tact. In occupational exposures this often requires chang-
ing jobs. Since contact dermatitis is an important
socio—economic disease, intensive study of the problem is
needed. While attempts are being made to develop new
procedures to replace the awkward and relatively im-
precise skin test, more research emphasis on treatment
and prevention is also required. Animal studies are aimed
at development of techniques for blocking reactivity to the
sensitizing material or contactant. Oral, topical, intrave-
nous and intramusclar applications of the contactant, or
combinations of them, are being studied as methods of
inducing unreactivity. Some regimens are effective, but
the effect is usually short-lived.

E. Allergic Drug Reactions

Allergic reactions to drugs take many forms and can
result from any one or any combination of the four broad
types of allergy. However, the pattern of reaction to any
one drug is usually fairly consistent.

Drug allergy is common, penicillin being the most com-
mon cause. One to three percent of patients treated with
penicillin have an allergic reaction to it. Moreover, a num-
ber of individuals show drug allergy to alternative anti—
biotics and therefore are placed in great jeopardy by
What are otherwise easily treatable infections.

Since almost everyone in this country has received
penicillin treatment at some time, this means that 1—3 per-
cent of the population is or will become allergic to it. Over-
all, it is estimated that allergic reactions occur in 0.1 to
1 percent of various drug treatment courses and that 5
percent of the adult population may be allergic to one or
more drugs, although as many as 15 percent believe them-
selves to be allergic to one or more drugs. This latter
statistic is of importance because many patients are un-
necessarily denied treatment with an effective drug be-
cause of their belief.

The drug itself, or perhaps more often a chemical de-

93

rivative of the drug, causes the reaction after combining
with some protein of the body. The drug or its derilative
is known asai ”and the drug- protein combination
asthe ‘eompleteanfigen. ” Apparently, the complete anti-
gen stimulates the production of specific antibodies and
the subsequent interaction of these two reactive molecules
leadste. allergic tissue damage or drug reactions.

In the case of most drugs, little is known of the immuno-
chemical mechanisms involved in the allergic reactions.
This is because a drug usually converts into numerous
complex products produced during its breakdown in the
body. The most thoroughly worked out system relates
to penicillin hypersensitivity. For penicillin G, four
haptens have been identified; one major and three minor.
Each may induce specific I gE antibodies but, in most cases,
only IgM antibodies in low concentrations were found.
These studies on the immunochemistry and immuno—
pathology of penicillin have required the development of
many sensitive techniques to measure and understand the
involved allergic mechanisms. These studies have also
provided a simple, rapid, safe and effective clinical test to
identify and screen out the potentially serious allergic re-
actors to penicillin. Continued research is needed to develop
similar tests for other drug allergies.

F. Conclusions

The current approach to allergic and atopic conditions
has largely emphasized identification of allergens, and
treatment with drugs or by desensitization. Considerable
improvement in medical management of these conditions
could result from increased understanding in several
areas. These include increased knowledge of the genetic
and developmental factors leading to atopy; the precise
nature of the increased production of IgE and its
binding to mast cells; the sequence of events leading to
mediator release; the mechanism of blocking with IgG an-
tibodies and the interactions of the immune and nervous

94

systems. Chemical analysis of the defined antigens are also
an essential component of these studies.

The' effectiveness and safety of desensitization proce-
dures and other therapy must be established in light of
our newer immunologic understanding of allergy. It is
equally important that non-effective and potentially im-
munologically dangerous practices be identified and dis-
carded. Adequate identification of potential allergic
components in commercial products should lead to a
national program of complete labelling of the contents of
such products. Standardization of diagnostic reagents with
newer biochemical and immunologic techniques is now
possible. An increased educational effort, at all levels of
medical and paramedical training, of immunologic dis-
eases is clearly necessary.

95

Chapter 7. AUTOIMMUNITY

While the immune system generally serves a protective
function against infectious agents and malignant cells,
under some conditions an/tihadieiandlarimmunelympho-
cytes mayreantmwith, and damagemermal-«body tissues.
This—process has been termed autoimmunity. The resul-
tant autoaggressive diseases, naturally occurring in man
and animals, are of considerable medical and economic im-
port. Autoimmune disease may also be produced experi-
mentally in laboratory animals by the injection of various
self-constituents. The resultant experimental diseases
closely resemble a large number of human autoimmune
diseases (AID) and have been useful in establishing the
pathogenesis of these disorders.

A. Mechanisms of Autoimmunity

Normally the immune system manifests an extraordi-
nary reluctance to react to “self” constituents. This self-
tolerance arises normally during fetal development and
persists throughout life. Autoimmune disease may result
from the acquisition of self-aggression or reacting to self
in at least three ways. (1) Certain tissue antigens may
have been sequestered or masked during development so
that “tolerance to them is never established. Should these
antigens subsequently be exposed to the lymphoid system,
an immune response may be initiated since the tissue anti-
gens are viewed as foreign. (2) Normal selffconstituents
may become altered in some way, for example, by the pres-
ence of viral components as a result of a persistent viral
infection (Fig. 21). This alteration, although slight, may
be recognized and thus initiate an immune response di-
rected at the altered tissue. (3) Exogenous antigens
bearing a close structural resemblance to normal tissue

96

   

.
.
(“—TESSue Cell
.<—- Virus
.
l C
C
:4 ®—Immu nologica“)!

\X Active. Ce,“

  

Fig. 21. What may turn out to be one of the most important
autoimmune reactions is thought to be due to alterations to
cells that have been affected by a Virus. In attacking the Viral
component, the immune reaction destroys the infected cells.

components may stimulate the immune system and cause
damage because the response also cross reacts with the
resembling normal tissue.

The preceding paragraph lists the three major classes
of mechanisms whereby tolerance to self is lost. In addi-
tion, there are specific conditions in which malfunction of
components of the immune system, or of related sub-

97

stances, is harmful. Some of the resultant damage is very
like that produced in the allergic diseases (Chapter 6).
Disease may thus result from injury to normal tissues
mediated by the activation of the accessory or effector sys-
tems which, once activated, are non—specific in their ac-
tion. A number of interactions between the complement
system and the blood clotting system occur normally; how-
ever, these interactions may go awry. For example, a syn-
drome of uncontrolled bleeding, called disseminated
intravascular coagulation, results from the exhaustion of
serum clotting factors, and is apparently due in some
cases to the immune response to certain infectious agents.

Breakdown in self-tolerance can lead not only to a direct
attack by the major components of the immune system,
antibodies and immune effector lymphocytes, but also to
attack by kinins and other components of the accessory
immune system. The effects of these malfunctions can be
extremely varied in severity, frequency, and in their mani—
festations. Because of this it is often difficult to diagnose
autoimmune diseases or to be certain that autodestruction
is indeed occurring. However, there is a considerable ac-
cumulation of evidence to support the contention that au-
toimmunity is a major cause of a number of serious or
fatal diseases and of innumerable chronic but less serious
disorders.

B. Autoimmune Disorders of Medical and Social
Importance

Autoimmune diseases vary in their medical, economic
and social impact. Some, like rheumatoid arthritis, are se-
vere and progressively cripple many individuals. Others,
like immune complex glomerulonephritis, are also com-
mon, but most frequently exist only as mild self-limited
diseases. Only exceptional cases develop into a severe
progressive disease.

Cortisone and other immunosuppressive drugs can di-
minish or arrest autoimmune diseases. However, the in-
herent risks of such therapy, often leaving the host with

98

a more lethal condition than that being treated, limit the
use of these drugs and emphasize the need for more spe-
cific therapy. Moreover, the physician hesitates to utilize
immunosuppressive agents in the ever-increasing number
of diseases in which an autoimmune component is sus-
pected, but not firmly established. Clearly, our limited
ability to identify such autoimmune contributions to dis-
ease reduces the effectiveness of the physician. To reduce
the impact of these diseases, the physician therefore needs
precise definitions of the autoimmune diseases and also
requires additional methods for treating them.

Table VII and the following paragraphs summarize
our current knowledge of some of the major autoimmune
diseases of man. It should also be mentioned that several
examples of autoimmune disease naturally occurring in
animals pose a severe economic problem. Animals affected
include horses (equine anemia), swine (hog cholera), d0-
mestic mink (Aleutian disease), sheep (scrapie) and dogs
(thyroiditis and lupus).

l. Immune complex diseases

The concept of immune complex disease has provided a
basis for the understanding of a number of diseases.
These include glomerulonephritis, rheumatoid arthritis,
systemic lupus erythematosus and polyarteritis nodosa.
In these conditions immune complexes are trapped in ves-
sel walls where they create inflammation (see also Chap-
ter 6). .

a. Glomerulonephritis in the United States is respon-
sible for approximately 12,000 deaths each year. Work
loss reaches 765,000 days annually, and earning loss more
than $15,000,000. Its cost is particularly great because it
frequently affects children and young adults. " In the vast
majority of instances, the cause of glomerulonephritis is
immunologic.

Glomerulonephritis is usually an immune complex dis-

ease, in that muonresultmmmg

WM». .1.

antigenfln‘tibody complexes. The injury results from the
deposition of. these circulating antigen-antibody 99m-

99

001

Table VII:

Some autoimmune disorders in man

 

Organ or tissue

Disease

Antigen

Detection of antibody“

 

Thyroid

Gastric mucosa

Adrenals

Skin

Eye

Kidney glomeruli plus
lung

Red cells

Platelets

Skeletal and heart muscle

Hashimoto’s thyroiditis
(hypothyroidism)

Thyrotoxicosis
(hyperthyroidism)

Pernicious anemia
(Vitamin B12 defic1ency)

Addison’s disease
(adrenal insufficiency)

Pemphigus vulgaris
Pemphigoid
Sympathetic ophthalmia

Goodpasture’s syndrome

Autoimmune hemolytic anemia

Idiopathic thrombocytopenic
purpura
Myasthenia gravis

Thyroglobulin
Thyroid cell surface
and cytoplasm
Thyroid cell surface
Intrinsic factor (I)
Parietal cells

Adrenal cell

Epidermal cells
Basement membrane

between epidermis-dermis

Uvea

Basement membrane

Red cell surface
Platelet surface

Muscle cells and thymus
“myoid” cells

Precipitin; passive hemagglutina-
tion; IF on thyroid tissue

IF on thyroid tissue
Stimulates mouse thyroid
(bioassay)

Blocks I binding of Big or binds
to I: B12 complex

IF on unfixed gastric mucosa;
CF with mucosal homogenate

IF on unfixed adrenals
CF

IF on skin sections
IF on skin sections
Delayed-type hypersensitive skin

reaction to uveal extract

IF on kidney tissue; linear
staining of glomeruli

Coombs’ antiglobulin test
Platelet survival

IF on muscle biopsies

IOI

Brain ? Multiple sclerosis

Spermatozoa Male infertility (rarely)

Liver (biliary tract) Primary biliary cirrhosis

Salivary and lacrimal Sjiigren’s disease

glands

Synovial membranes, etc. Rheumatoid arthritis

Systemic lupus
erythematosus (SLE)

Cytotoxicity on cultured cere-
bellar cells
Agglutination of sperm

Brain tissue
Sperm

IF on diverse cells with abundant
mitochondria (e.g., distal tubules
of kidney)

IF on tissue

Mitochondria (mainly)

Many: secretory ducts,
mitochondria, nuclei, IgG

Fc domain of IgG Antiglobulin tests: agglutination
of latex particles coated with
lgGs, etc.

Many: DNA, DNA-protein, Precipitins, IF, CF, LE cells
cardiolipin, IgG,
microsomes, etc.

 

‘IF=immunofiuorescence staining, usually with fluorescent antihuman Igs
CF=complement fixation
Based on Riott, I. Essential Immunowgy. Blackwell, Oxford, 1971.

plexes 1n the filterifig vessels of the kidney glomeruli. An—
tigens implicated in human glomerulonephritis include
foreign serum, drugs, streptococcal antigens, malarial an-
tigens and hepatitis and measles viruses, to name a few.
Thus, glomerulonephritis includes a group of diseases of
“self-injury” resulting from the immune response to for-
eign antigens, rather than a true autoimmune (anti-self)
response.

Immune complex glomerulonephritis is common also in
domestic and laboratory animals. In the best studied in-
stances, viral infections appear to be involved. Conceptu-
ally, viruses provide an ideal source of antigenic material
capable of causing immune complex disease. If the specific
antigen causing immune complex disease could be identi-
fied, it would be possible to manipulate the immune re-
sponse to terminate the formation of complexes. If the
antigen were from a Virus, it might be possible to immu-
nize patients in order to eliminate the virus.

b. Systemic lupus erythematosus (SLE) is an immu—
nologic disease with arthritis. skin rashes, fever. and
ple‘urisywas common symptoms. The serum of patients
with SLE contains a variety of autoantibodies reactive
with” cell constituents. If immune complexes resulting
from the interaction of autoantibodies With self constitu-
ents are deposited in the kidney, a severe glomeruloneph-
ritisiresults. The disease is potentially fatal when either
the kidneys or the central nervous system are affected.

SLE is primarily but not exclusively a disease of young
women. Virus-like particles have been found in the lym-
phocytes and endothelial cells, raising the possibility of a
latent virus infection. An SLE-like condition can also be
induced by certain drugs.

There are several unanswered questions about SLE.
What are the genetic predisposing factors? Is SLE initi-
ated by a chronic virus infection? If so, it would become
one of a group of diseases, sharing similar features, called
“slow” virus diseases. How does autoimmunity relate to
the development of the malignant lymphoma which occurs
in this disease?

102

The discovery that certain strains of New Zealand mice
spontaneously develop a disease which appears to dupli—
cate SLE in man has provided a major step forward.
These New Zealand mice are relatively resistant to toler-
ance induction to a variety of antigens and lose tolerance,
including tolerance to self, rapidly. Antigen-autoantibody
complexes, especially anti-nucleoprotein complexes, accu-
mulate in their kidneys and lead to glomerulonephritis.

c. Rheumatoid arthritis (RA) is a common disease cur-
rently afflicting between 2 and 3 million patients in the
United States. It produces a crippling inflammation of the
joints, especially of the hands, wrists and knees. This dis—
ease progressively worsens over 10 to 30 years and ac-
counts for at least 12.2 million work days lost yearly at
a cost of 3.65 billion dollars (Fig. 22).

 

Fig. 22. Hands of a 45-year-old man with rheumatoid arthritis.
Note the nodules in the skin which are common in severe and
progressive disease and contain lymphocytes, plasma cells, and
macrophages. The joints of the wrist and base of the fingers
are swollen as are the tendon sheaths. (From Rodnan, Gerald
R, Primer on Rheumatic Diseases, Journal of the American
Medical Association, April 30, 1973, reprinted with permis-
sion.)

103

RA is a systemic disorder. In addition to the joints, the
eyes, lungs, heart, spleen, skin, muscles and peripheral
nerves may be affected. The most striking immunological
response in RA is the presence of special antibodies known
as rheumatoid factors. These are, in effect, antibodies
against gamma globulin or anti-antibodies.

The arthritic joint fluid contains both rheumatoid fac-
tors and IgG. Thus, immune complexes are formed. In-
flammation results and the synovium or lining membrane
becomes heavily infiltrated by cells involved in the im-
mune response—plasma cells and lymphocytes. The im-
munological reaction proceeds in the affected synovium
itself as evidenced by the fact that the lymphoid cells of
cultured synovium produce gamma globulin, and comple-
ment levels in the synovial fluid are depleted.

The antigen which is primarily responsible for this im-
munologic activity is unknown. It is important to deter-
mine whether it is an infectious agent, and if so, to identify
it and terminate the infection.

2. Multiple sclerosis—altered self-antigen

Multiple sclerosis (MS) is a disease which affects young
adults, 20—40 years of age. This disease is progressive in
an irregular manner. Muscular weakness and visual dis-
turbances are common. Animals immunized with nerve
tissue develop a neurological disease called experimental
allergic encephalomyelitis (EAE). The similarity of the
two diseases suggests that MS is an immunologic disease.
Blood serum of animals with EAE and patients with MS
contains an antibody which can injure cultured living
brain cells. Furthermore, the spinal fluid contains an in-
creased amount of immunoglobulin which is apparently
synthesized in the central nervous system.

Answers to several questions concerning MS are ur-
gently needed. What is the antigenic constituent against
which the immunoglobulin in the spinal fluid is directed?
Does the tissue in the multiple sclerosis lesions in the cen-
tral nervous system synthesize the antibody?

Epidemiologic studies are consistent with the likelihood

104

that an environmental factor acquired before adolescence
plays an important role in MS. This factor is most likely
to be a persistent or “slow” virus infection, similar to that
demonstrated in Kuru, an MS-like disease of certain na-
tives of New Guinea, although such a virus in MS has yet
to be isolated. Such an infection would presumably lead
to the accumulation of “altered” antigen, which would
then stimulate an autoimmune response. Genetic factors
are also being implicated. Affected individuals are apt to
belong to a particular HLA tissue type.

3. Autoimmune thyroid disease—unmasked self-antigen

Hashimoto’s disease and Graves’ disease, two forms of
thyroid disease, are believed to be consequences of auto-
immune reactivity (Fig. 23). Patients with Hashimoto’s
disease have a general malaise lasting several years and
a moderately enlarged firm thyroid. On histological sec-
tion, the thyroid is characteristically infiltrated with
lymphocytes. Graves’ disease typically induces weight loss
and nervousness in young women. Metabolic disturbances
are more severe than in Hashimoto’s disease but the
histological pattern may be similar.

It has become increasingly evident that immunologic
processes play a major role in these diseases of the thyroid
gland. Immunization of animals with a protein of the thy-
roid called thyroglobulin produces chronic inflammation
of the thyroid, i.e. experimental allergic thyroiditis
(EAT). EAT closely resembles thyroiditis in man. Both
cellular and humoral responses against thyroglobulin ap-
pear to be necessary for maximum injury; presumably the
same is true for human thyroiditis. The deleterious effects
of antibody may be exerted through the deposition of
thyroglobulin-antithyroglobulin immune complexes which
injure the thyroid.

Elucidation of immunologic mechanisms in the thyroid
is bringing us closer to an understanding of the metabolic
abnormalities of this gland. Hypothyroidism often follows
chronic thyroiditis. Serum of patients with hyperthyroid-
ism contains a long-acting thyroid stimulator (LATS),

105

 

 

 

 

 

4o — —
(D
Z — —
Q
l— _
o 30 _
<3:
LIJ
O: _ _
DJ
2 20 — _
L‘.
U)
0 " _
o.
'— lO —— __
Z
LIJ
C.) _ _
o:
LIJ
0- 0 I I I I I I
20 —29 40-49 6 0-69 8 0 ~89
30-39 50-59 70—79
AGE GROUPS

Fig. 23. Incidence of thyroglobulin auto-antibodies in males
(A—A) and females (0—0) in relation to age. (Modified
from Goodman, M. et al., Arch. Gen. Psychiat. 8: 518, 1963.)

which resembles a thyroid-specific autoantibody. It Will
be important to develop an antibody against LATS that
would neutralize LATS Without causing any stimulat-
ing effects of its own.

4. Drug purpura and hemolytic anemia—normal cells
affected as “innocent bystanders”

While we are accustomed to the beneficial efiect of
drugs, such as penicillin or aspirin, their effect on some
patients may be devastating. This is because, like any for-
eign substance that enters the body, drugs may function
as antigens. The immune system then responds by the pro-
duction of antibodies, and less frequently, immune lym-
phocytes (see also Chapter 6).

106

When a drug-antidrug antibody reaction involves the
surface of circulating blood cells, destruction and hence
deficiency of that blood cell type may ensue. This process,
termed the “innocent bystander” reaction, may clinically
result in purpura (hemorrhage) or anemia when plate-
lets or red cells, respectively, are involved (Fig. 24). Al-
though most cases recover over a few weeks time after
the drug is withdrawn, some individuals may be severely
and even fatally affected. A number of the drugs involved
in this type of reaction are clinically important and com-
monly used. Quinine and quinidine in purpura, and peni-
cillins in hemolytic anemia are examples.

Although bone marrow failure is a not infrequent con-
dition, only a small proportion of cases can be attributed
to sensitization to a specific drug. Diagnosis of autoim-
mune blood disorders is relatively simple if the antigen
can be identified since the antibody can then be detected
and measured. If the antigen is unknown, chances of dem-
onstrating antibody are slight. It would be of some con-
siderable importance to know if the majority of cases of
bone marrow failure are due to autoimmunity or to some
unrelated cause.

Administration of specific antigens is a promising new
approach to treatment that deserves increasing attention.
The rationale behind administration of antigen as a ther-
apeutic measure includes (a) production of antibody
with protective (blocking) properties, (b) desensitization
of sensitized lymphocytes (see also Chapter 6), (c) rein-
stitution of unresponsiveness, and (d) production of im-
mune complexes which are soluble and therefore less
likely to produce tissue injury.

Passive administration of blocking antibody may also
prove to have therapeutic value. This would not only pro-
vide the host with a temporary immunity, but would also
take advantage of the exquisite capacity of antibody to
inhibit immune responses (see also Chapter 2). A critical
area of future research is the definition of the conditions
for the production of antibodies which can “block” auto-
immune processes but not cause damage themselves.

107

00 Platelets

   

\ l/
+:/D/ru3\/:
mated,
\ NI C \ l //
\ "‘ \\ / F—DY‘U adsarbed
/ \\\ _ “E onto platelet

Rs 000

// / \

\

Ta 0 0 0

\k:\\ ab 0< ? :0? Macrophage

//

Fig 24. In drug-induced autoimmune reactions the drug is ab-
sorbed onto the surface of a cell. Antibody combines with the
drug and the cell carrying the antibody- antigen complex is
removed. This can cause severe deficiencies of circulating
blood platelets, which leads to bleeding diseases, or of red
blood cells, which leads to anemia.

C. Summary and Prospectus

Concepts of autoimmunity are undergoing dynamic
change. Increased understanding has resulted from inten-
sive study of experimental animal models of human
disease. The mechanisms of immunologic tolerance to self-

108

antigens and loss of tolerance leading to autoimmunity are
beginning to come into focus. In many of the examples of
immunologic disease in man discussed in this text, persis-
tent virus infection is believed to be of importance. One
of the challenges for the future is the characterization of
viruses and other pathogenic agents linked to autoimmu-
nity.

The prospects for prevention and treatment of autoim-
mune diseases are good. Numerous diseases similar to
those of man occur naturally or can be induced in animals,
thus affording opportunities for more detailed studies.
Most encouraging is the finding that the experimental dis-
ease is usually self-limiting and that the affected animal
recovers. Allergic encephalomyelitis can even be pre-
vented, by the prior injection of antibody, thus providing a
possible model for the treatment of certain human dis—
eases.

109

Chapter 8. TRANSPLANTATION AND
CANCER IMMUNOLOGY

As described in previous chapters, one of the primary
functions of the immunologic defense system is to recog-
nize and attack foreign invaders of the body. This in-
cludes foreign tissue. The attack is beneficial if the foreign
tissue is cancerous but adverse if the foreign tissue is a
therapeutic skin transplant or a transplanted kidney.
Thus, medical approaches to attack and rejection are simi-
lar for both types of problems, but the objectives are
diametrically opposed. One set of studies, i.e. those on can—
cer, attempts to enhance the immune reaction. The other
seeks methods to retard the reaction or to specifically
neutralize it so that the transplanted tissue or organ will
be tolerated by the body’s defense mechanism.

Key components of this defense system are lympho-
cytes present in the blood, bone marrow, thymus, lymph
glands, spleen, lungs, and other areas of the body. The
lymphocytes of the patient receiving a kidney transplant
react against foreign substances (antigens) on the trans-
planted cells, and the immunological reaction leads to de-
struction or “rejection” of the transplant unless the graft
is from an identical twin, or unless some kind of immu-
nosuppressive treatment is given to lower the activity of
the patient’s defense system (Fig. 25).

In the case of cancer, the cancerous cells resulting from
the malignant transformation of the normal body cells
have become antigenically different and are recognized as
foreign by the immune system of the patient. If the proper
sort of immunologic responses are initiated, the trans—
formed cells may be destroyed. This may occur frequently
throughout our lives. In the patient who develops cancer,
these immunologic responses are often ineffective in bring-
ing about rejectiOn of the original cancer, although they

110

lflDNEY CELL

   

tYMPHOCYTE

Fig. 25. Lymphocytes of the patient receiving a kidney transplant
react against tissue antigens on the transplanted cells, and the
immunological reaction leads to destruction or rejection of the
transplant unless some form of immunosuppressive treatment
is given.

may slow its rate of growth and, occasionally, they appear
to produce a spontaneous regression. The question is unre-
solved as to whether clinically detectable tumors represent
only the rare occasions on which antigenic cancer cells es-
cape the rejection response, or whether the immune re-
sponse has become ineffective in destroying antigenic cells
as they arise, i.e., before the cancer has a chance to grow
to detectable size.

Both transplantation and cancer immunology therefore
depend upon two common fundamental features: (1) Cells
possess characteristic antigens on their surfaces. (2) The
host is able to recognize and attack cells that bear anti-
gens differing from those of his own normal cells.

The transplanted tissue carries an impressive variety
of antigens. Some are common to all members of the spe-

111

cies, some are characteristic of cells of the particular in-
dividual and some are specific for the organ or tissue. A
cancer cell possesses not only the normal complement of
antigens of the host and of the organ from which it de-
veloped, but a new antigen, or series of antigens, found
principally on the cancer cell and, in some instances, on
fetal cells of the host’s species.

Since the history and philosophy of studies of trans—
plantation and tumor immunity are so interrelated and the
cellular and antibody responses mounted against one seem
to resemble the responses against the other, this chapter
summarizes information about both transplantation and
tumor immunity and considers issues common to both.

A. Transplantation
1. Blood transfusion

Transfusion of blood and blood products constitutes the
, most frequent and most successful clinical application of
transplantation in medicine to date. Safe transfusion was
not possible, however, until we learned to identify and
match the major blood cell antigens of the donor and re-
cipient in such a way that the transfused cells were not
seen as foreign and destroyed. The importance of blood
transfusion as an essential life-saving procedure is well
known in surgery, in therapy of obstetrical complications,
in treatment of medical emergencies, and in hastening
patient recovery.

The basic research that was essential to defining the
ABO blood group system has also provided a major impetus
to progress in its own field and in significant related fields.
Typing of the blood groups for successful blood transfu-
sion hastened recognition of the possibility of tissue typing
and provided a basis for development of its technology.
Such studies also formed the basis for our understanding
of the genetic compatibility essential to successful organ
transplantation. These studies have also provided a power-
ful tool for the analysis of certain problems of anthro—
pology and population genetics, and they have led to a

112

further understanding and improved treatment of many
diseases.

2 . Skin transplantation

Transplantation of the skin is, perhaps, the oldest form
of tissue transplantation and it is used extensively today,
especially in the treatment of burns. Though autografts
(transplants from one part to another of the same body)
are almost always successful, transplantation from one
individual to another usually results in rejection. Several
advances in recent years give promise of better results.
These include tissue typing and the donation of skin from
family members to utilize genetic compatibility, improved
' control of infection and the cautious use of drug therapy
to prevent rejection. Due to improved methods for long-
term storage of skin (from cadavers) at lOW temperatures,
banks of skin for resurfacing the critically burned pa-
tient can now be seriously considered.

3. Transplantation of the cornea

Over 2,000 transplantations of the cornea—the trans-
parent membrane of the eye—are performed in the United
States each year. Improved microsurgery has made this a
highly successful technique for curing one form of blind-
ness. Unlike most tissues, the cornea is normally not per-
fused with blood, nor does it have lymphatic drainage, and
thus it does not normally encounter circulating lympho—
cytes. Nevertheless, a proportion of such operations fail
because of immunologic rejection. If the rejection reaction
is treated early, damage to the transplanted cornea is usu-
ally not permanent. Several of the problems common to all
transplantation operations apply to corneal transplants.
Choosing a suitable donor (cadaver) for the patient who
needs a corneal transplant, early tests to detect and prompt
treatment for rejection response, and preservation of
corneas at low temperature (eye bank) are measures that
promise improved results.

113

4. Organ transplantation

Many thousands of people die each year because of loss
of function in a single organ. Countless other people are
disabled. Although prevention of the original disease
would be preferable, a successful transplant can restore
the recipient to a near normal state of health and even to
full rehabilitation. The chief problem in organ transplan-
tation continues to be avoidance of rejection. General
measures being taken to escape rejection include the
preservation of donor organs until the appropriate recipi-
ents are located and prepared for surgery, improved
techniques for selection of donor-recipient pairs to reduce
the likelihood of rejection, and increasing the potential
donor organ pool by improved interchange between distant
transplant centers. These procedures apply to all forms
of organ transplantation.

a. Kidney transplantation. End stage kidney disease
kills an estimated 12,000 Americans each year. Dialysis
by the artificial kidney can sustain patients with renal
failure for long periods, but at considerable medical,
psychological and economic cost. Transplantation of the
kidney has proved to be the preferable mode of therapy
when rehabilitation of the patient, amount of time, includ-
ing medical attendants required for patient maintenance,
and costs are considered. When the donor is a sibling shar-
ing the same set of major transplantation (HLA) anti—
gens, over 90 percent of the transplants survive more than
2 years (Fig. 26). Unfortunately, few kidney patients
have a suitable sibling to act as a donor and must rely on
high doses of powerful drugs to control the immune re-
sponse to protect the transplant from rejection.

The actual proportion of incompatible kidneys surviv-
ing depends upon many variables, including the age and
clinical state of the patient. Success rates of over 7 0 per-
cent of kidneys transplanted from cadaveric donors are
reported in selected series.

The steady improvement in kidney transplant survival
in recent years is due to several factors: (1) improved

114

 

IOO

 
 

match

    

 

Com p\e‘c e—

 
 

 

 

 

.J
E
G>C Partlal match
3
U) 50 — . _
uJ MLSmRJLClfl
2:9
,—
Z
LIJ
Q
0:
E
l l l
0 2 4 6
YEARS

Fig. 26. Survival of kidneys in relation to degree of HLA match—
ing. Complete match (siblings) = all HLA antigens identical;
partial match (siblings and parent to child) 2 only antigens on
one chromosome (haplotype) identical; mismatch (unrelated)
= all HLA antigens different. (Data taken from J. Dausett
and J. Hors, Transpl. Proc. 5: 223, 1973.)

medical care for the patient both before and after the
transplant; (2) the use of tissue typing techniques to
match donor and recipient and thus reduce the rejection
factor; and (3) early detection and treatment of rejection
episodes and more skillful use of drugs to prevent rejec-
tion.

A major' obstacle to successful transplantation of the
kidney is that the drugs taken to suppress the immune re-
sponse and thus prevent rejection are a major cause of
complications (Fig. 27). These drugs do not selectively
suppress foreign cell rejection but instead inhibit the func-
tioning of the total immune system. In addition to increas—
ing the chances of infection, they also diminish the body’s
immune surveillance against malignant cells. A higher
percent of patients,transplanted and maintained on drugs
designed to suppress the immune response, have developed
some form of cancer than in the normal population.

115

CAUSE OF NONvFUNCTION 0F 1,365 RENAL TRANSFLANTS

 

Uretem Obstruction

Contest Necrosis

Arterial Thrombosis

Venus Thrombosis

Sum. 1121., & Szpsis

Surgics! GI Rejection

Surgical & Sepsis

Tubular Necrosis

Reieclinn & Sepsis

Sepsis

Suvgical

Unknown Cause

Rejection

 

 

 

Fig. 27. From US Kidney Transplant Fact Book, Information
from ‘ACS/NIH Registry 1972, DHEW Publication # (NIH)
73—335.

The following data from a reported study emphasizes
one justification for preference of transplantation over di-
alysis as the definitive mode of therapy where transplan-
tation is possible (Table VIII). In a group of 100 patients
(50 of whom received a transplant, 50 of whom were only
maintained by the artificial kidney), the cost was $1.86
million less for the transplanted than for the artificial

Table VIII: Comparison of cost of 50 transplant and 50
hemodialysis patients at one center over a 4-year period
(1968—1971)

Transplant Hemodialysis

(50 patients) (50 patients)
Total cost (4 years) 750,000 2,600,000**
Mortality 20% 26%
Gainfully employed 91% 34%
Receiving public assistance 0 80%

Total dollar savings: 1.85 million dollars in 4 years
"Not including public assistance.

kidney group. The mortality in both groups was the same.
However, 91 percent of the successfully transplanted pa-
tients were able to work, while only 34 percent of the
patients receiving only artificial kidney treatment were
gainfully employed, and some form of public assistance
was needed for 80 percent of the latter. None of the
successfully transplanted patients required welfare.
Transplantation, if we can abrogate rejection, provides a
definitive mode of therapy without continuing need for
major medical attention or expense.

b. Heart transplantation. Approximately 200 heart
transplants have been performed in the past four years.
Of 28 surviving patients, four have now lived more than
four years following transplantation. In certain centers
specializing in this procedure, the survival percentage ap-
proaches that of kidney survival following transplantation
from an unrelated, recently deceased donor. Problems of
threatened rejection of the heart transplant are com-
pounded because end-stage heart disease patients do not
have a support system similar to hemodialysis, which
will maintain the patient until a suitable donor can be
found, as in the case of kidney transplant patients.

0. Bone marrow transplantation. The bone marrow is
the source of cells which give rise to the red blood cells,
lymphocytes, and other cells of the blood. Transplanting
bone marrow is a procedure which would have immense
applicability if it could be accomplished without danger
to the patient. The marrow transplantation procedure is
relatively simple technically. Bone marrow cells are ob-
tained with a needle from certain bones of the donor and
are then injected into a vein of the recipient. If the trans-
plant is successful, the injected cells find an environment
inside the bones of the patient, multiply rapidly, and re-
plenish the blood of the patient. Between 1951 and 1968
more than 200 human bone marrow transplantations were
attempted. Only two of these were apparently successful.
In 1968 successful transplantation was reported in two
children with an otherwise fatal lymphocyte deficiency
disease. In these children, sophisticated techniques for

117

pairing donor and recipient were employed for the first
time. The application of newer techniques has improved
markedly the outcome of this procedure. Reports between
January 1968 and November 1974 indicate over 200 pa-
tients received bone marrow transplants, 25 percent of
which have proved successful.

d. Liver transplantation. Transplantation of the liver
has major technical problems. One hundred and seventy-
two liver transplants have been reported in the past
several years. While early results were disappointing and
numerous technical difficulties had to be overcome, one pa—
tient is surviving after four years and fourteen patients
are now living over one year after transplantation. One
major difficulty is the necessity for speed since liver cells
deteriorate very rapidly after death of the donor.

e. Lung transplantation. Transplantation of the lung
presents the most diflicult immunological and technical
problems of all organs. Only two patients have survived
significant periods of time; one of these lived ten months.

f. Transplantation of other organs. Several other or-
gans have been transplanted on an experimental basis;
these include the pancreas, spleen, intestines, tendons,
bone, cartilage, blood vessels, and the larynx. To date, the
results obtained have not been encouraging. However, it
should be remembered that, while the success rates for
some organs are unimpressive, the transplant patients
who survive have been salvaged from otherwise certain
death. Furthermore, the history of transplantation has
shown an increasing survival rate as techniques improved.
The success of kidney transplantation bears witness to
that.

5. Special needs of transplantation

Transplantation, when successful, is one of the most dra-
matic forms of treatment in all of modern medicine. The
recipient of an HLA identical kidney can, for example,
reasonably expect discharge from the hospital within
2 weeks and can return to a fully productive life within
two months. A nUmber of such patients have even experi—

118

enced parenthood following the operation. This is in sharp
contrast to the repeated failures experienced with trans-
plantation of some other organs and even for the trans-
plantation of non-identical kidneys where a proportion are
complete failures or function for only short periods. Four
elements are needed before transplantation can be uni-
versally successful. These are improved matching, im—
proved methods of avoiding rejection, long-term organ
preservation, and life support systems (comparable to that
afforded by kidney dialysis) for diseases affecting other
organs.

Better matching includes tissue typing donor and re-
cipient for more HLA antigens. It also requires a better
understanding of other factors closely linked to HLA
which are not detected by straightforward tissue typing.
One of these factors is known to stimulate lymphocytes to
divide; another stimulates the ability to kill cells of the
transplant. The information, that there are several dis-
tinct but in some way related genes crowded together on
the same chromosome, is very new. A novel form of col-
laboration between immunologists in the form of interna-
tional workshops is helping decipher these new facts as
rapidly as possible. The support of the National Academy
of Sciences, National Research Council and of the Na-
tional Institute of Allergy and Infectious Diseases has
helped initiate and maintain this essential collaboration.
Matching could become relatively simple, for example, if
some components of the histocompatibility complex proved
to be more immunogenic than others. There has as yet
been no occasion to test this possibility, but it is known
that the matching requirements for skin transplantation
and those for heart, kidney or ovary are not identical, and
also that genes which are strongly expressed on some tis-
sues are suppressed on others. Thus, matching for differ-
ent types of tissues or organs may require different types
of tests and different reagents. This approach is being
used for selection of bone marrow donors when there are
no HLA identical family members, but it has not yet been
extended to other forms of transplantation.

119

Selective immunosuppression may come from the joint
efforts of pharmacologists and immunologists and may be
directed towards the deactivation or destruction of specific
lymphoid cell types, e.g. T helper cells, while leaving other
types of cells, e.g. T memory cells and B cells, intact. Inten-
sive collaboration between immunologists and pharmacolo-
gists is presently rather limited. However, from such
studies has recently come the realization that certain
drugs, not previously known to be immunosuppressive are
extraordinarily effective in blocking tissue cell destruction
by lymphocytes.

The immunologist has been able to separate tissue cell
destruction by lymphocytes into phases, and to design rela-
tively simple assays for measuring activity in each phase.
This information will allow the pharmacologist to set up
rapid and inexpensive procedures to screen compounds for
activity against the individual phases of lymphocyte-
mediated killing, thus making more probable the discov-
ery of new and more specific pharmacologic agents.

A completely different approach has also been taken,
based on the ability of antibody to block immune responses.
In this situation, called immunologic enhancement, anti-
body directed against a tissue is injected into an animal
together with cells from tissue of the same type. The in-
jected antibody specifically prevents the host from making
an effective response against the tissue. Initially discovered
in studies of immunity to tumors, this procedure has now
been extended to the prevention of rejection of renal grafts
in animals, and in man in the very few instances where it
has been tried. This form of treatment is highly selective
since other immunological response capabilities are left
intact. Suppression by suppressor T cells can also be con-
sidered for prevention of rejection of transplants. If suc-
cessful, this would provide a form of selective suppression
that should be self-propagating in the presence of antigen.
Again, this is a very new topic and such investigations, at
present, center around identification and isolation of the
suppressor T cells.

Avoidance of recognition could encompass two areas.

120

The first of these is selection of donors on the basis of
genetically controlled immune response capacities of the
recipient. Some animals will experience a strong response
to foreign red cells, while other animals, identical in many
respects, Will make a feeble response. The same appears to
be true with respect to the response to skin and possibly
organs. Given a choice, it makes good sense to select a
graft that will provoke only a feeble response in the recipi-
ent. Thus, selection on the basis of blind spots in the recog-
nition mechanism of the recipient would greatly reduce the
intensity of attempted rejection, permit marked reduction
in the amounts of drugs required to control rejection, and
therefore greatly extend the safe range of transplanta-
tion. This type of donor-recipient selection could profit-
ably be combined with the second form of avoidance of the
immune response; tolerance induction. Chances of such a
combined approach seem excellent since it is known that
tolerance to transplants can be attained with ease in some
experimental combinations, While in other combinations,
tolerance is established with considerable difficulty. This
type of approach has great potential application but no
attempts have yet been made because of the lack of precise
knowledge of immune response genes in man and because
we do not yet know how to induce the desired type of
tolerance in man. Some very significant research awaits
appropriate attention.

B. Cancer Immunology

Evidence is strong that lymphocytes react not only
against established tumors but that they play a major
role in eliminating many tumors before they gain a foot-
hold. This latter role has been termed “immunological sur-
veillance.” One of the major evolutionary pressures for
the development of lymphocytes and the cellular immune
system may have been to eliminate those thousands of
cells that daily undergo mutation within our bodies. If the
immune system does provide such defenses, why then does
an individual ever develop cancer?

121

Extensive data show that patients, even with advanced
cancer, do have potent lymphocytes capable of destroying
their own tumor cells growing in the test tube. Unfortu-
nately, most cancer patients also have substances in their
blood which inhibit their lymphocytes from killing their
tumor cells in the body. These substances are known as
“blocking factors” and they appear to consist in part of
specific antibodies, complexed with tiny fragments of tu-
mor cell. Therefore, the patient carrying a cancer has two
competing forces at work: (1) the lymphocytes which
carry the potential to kill the tumor cell, and (2) blocking
factors in the blood which prevent these lymphocytes from
acting. The second mechanism may be a major reason why
the immunological system, or immune surveillance, does
not always work successfully against tumors.

Elimination of the “blocking factors” would be one way
to augment the anti-cancer immune defenses. Another
would be to stimulate the immune lymphocytes directly so
that their attack on tumor cells would be more effective.
Encouraging progress has been made in this latter area.
Skin sensitizing agents such as dinitrochlorobenzene
(DNCB) and a living bacterium, Bacillus Calmette—
Guerin (BCG), are potent stimulators of lymphocytes.
Injection of these substances into established tumors have
so augmented the immune defenses, particularly in the
area around the injection site, that the tumor has re-
gressed (Figs. 28, 29). In leukemia, the use of BCG in
combination with other drugs has led to great improve-
ments and often “cures” for as long as eight years. It
cannot be determined, at this point in time, whether these
patients have been permanently cured, but, so far, they
show no signs of recurrent disease. Other organisms that
have given preliminary evidence of stimulation are C.
parvum and the organism causing whooping cough, B.
pertussis. Intensive research efforts are now underway to
improve this form of therapy, to evaluate its long-term
effects, and to understand its true mode of action.

Immunology has also been very useful in the diagnosis
and prognosis of certain cancers. Some cancers release

122

 

Fig. 28. A. The patient has an extensive skin eruption likely to
develop into cancer. He is treated with a drug that sensitizes
his skin. B. In responding against a very dilute solution of the
drug he is also induced to respond against the affected skin
cells. Klein, Cancer Research 29: 2351, 1969.

123

 

Fig. 29. (a) Leg of a patient with melanoma, a skin cancer usually
arising from a hairy mole. The patient has begun a course of
treatment with modified tubercle bacilli (BCG vaccine). (b)
gamle patient after 8 months of treatment (Courtesy Dr. H. F.

eig er).

125

 

minute amounts of antigen into the blood. Detection of
these antigens by new, exquisitely sensitive, immunologi-
cal assays often provides the earliest clue to the pres—
ence of cancer. After surgical removal of the cancer, these
antigens disappear from the blood and do not reappear
unless the tumor has been incompletely excised or has re-
curred. Thus, follow-up of post-surgery patients with
tests for these antigens provides an excellent way to de-
tect recurrent disease before the physician can otherwise
detect it. So far, only a limited number of tumor antigens
can be detected, although there are indications that other
tumors do release antigens into the blood. Thus much work
remains to be done in this area of research.

Finally, the most exciting of all possibilities is specific
vaccination against cancer so that it, like smallpox, polio,
etc., may not have to be cured, but rather will be pre-
vented and become a disease of the past. This is by no
means a fanciful dream. Medical science is able to im-
munize against smallpox because all smallpox viruses
share antigens with a closely—related virus, cow-pox virus,
which is used as a vaccine. Similarly, immunology has
shown that tumors of a given type, say all cancers of kid-
ney, or all melanomas, share “common” antigens. Our
ultimate hope is to isolate and purify the “common”
antigens of tumors, or of the causative Virus, and
then develop appropriate materials to vaccinate the popu-
lation against a mixture of these antigens. It is believed
that this would give protection against the emergence of
tumor cells in the body—in a sense greatly augmenting
the natural “immune surveillance” system. Some of these
antigens have been isolated in animal studies and have
been successfully used as vaccines. This approach has al-
ready been used to eliminate the economically significant
cancer of chickens (avian leukosis). The ultimate applica-
tion of these procedures to man is conceivably attainable
through future research.

In summary, the immune system plays a major role in
organ transplantation and in cancer. In the former, we
have prolonged graft survival by matching the antigens

126

of the donor to those of the recipient and by generally
weakening the immune system with drugs. Our future re-
search efforts must primarily be directed at better antigen
matching and at blocking only that aspect of the immune
system which specifically attacks the graft, leaving the
patient’s immune system intact to fight infections. Stimu-
lation of graft-specific blocking antibodies might also
be useful here. In cancer immunology we have detected
tumor-specific antigens and know that at least two com-
peting immunologic forces, the immune lymphocyte and
blocking factor, play a great role in the course of the tu-
mor. Progress has been made, but research remains to be
done to use antigen-detection in diagnosis and prognosti-
cation of cancer, to stimulate host lymphocytes to attack
the cancer, to eliminate blocking factors and their deleteri-
ous effects on the host’s lymphocytes, and to develop means
to vaccinate the population against tumor antigens.

127

Chapter 9. THE FUTURE OF
IMMUNOLOGY—ALMOST
WITHIN OUR GRASP

A characteristic of immunologists is their vocabulary,
not only in the jumble of terms and phrases, but also in
the frequency with which they admit “we think,” “we
believe,” “we hope,” and the ever—present “if.” This
chapter* is predicated on the eventual elimination of “if”
and assumes that, based on the mass of solid information
we now have, many goals which we are projecting can be
attained. It will define the areas of great importance and
it will attempt to define the problems faced and the means
to prevent, ameliorate, or cure relevant diseases (Table
IX).

A. Immunological Manipulations
1. I mmunotherapy

Immunotherapy, whether of cancer or of other diseases,
can fall into any of three categories: suppression, aug—
mentation and reconstitution.

a. Immunosuppression (Table X). One of the oldest
known forms of nonspecific suppression is reticulo-
endothelial blockade where the individual receives a mas—
sive dose of a poorly metabolized product such as carbon,
colloidal gold or lipid. The macrophages and fixed phago-
cytic cells become so overloaded with the inert material
that they cannot respond to a subsequent challenge with
antigen. The condition is rapidly reversible. This ap-
proach could be revitalized through the use of short-lived
isotopes in colloidal suspension to increase the effect and
extend its duration.

*which is the sole responsibility of the Editor

128

Many drugs and gamma or x-irradiation reduce immu-
nologic responsiveness. Best known are x-rays, and the
y-rays from a cobalt or other nuclear fission source, the
corticosteroids, and many of the drugs such as 6-
mercaptopurine and cyclophosphamide commonly used in
the chemotherapy of cancer. Alcohols and surface anes-
thetics can, under certain conditions, have a marked effect
on immunologic reactions. Anti-thymocyte and anti-
lymphocyte sera are very potent immunosuppressive
agents in mice, especially when combined with thymec-
tomy. Administration of drugs in this category is essential
for the survival of almost all transplanted tissues and is
being explored in the control of autoimmune reactions.
However, the side-effects can be awesome. Organisms not
normally regarded as pathogenic frequently cause grave
morbidity leading to eventual death.

b. Augmentation. This is traditionally the most widely
used form of immunologic manipulation; the use of vac-
cines. It is typified by the injection of a specific antigen or
collection of antigens to provide immunity against com-
mon microbial invaders. This form of therapy (prophy-
laxis) has its greatest value in developing countries faced
With endemic or epidemic infections, and in the protection
of children against common childhood diseases. Aerosols
for vaccination against respiratory tract pathogens and
orally administered vaccines for the protection of the gas-
trointestinal tract are examples of newly introduced pro-
cedures. These procedures carry a certain risk of
morbidity or even of mortality, especially in immunologi-
cally handicapped individuals, so that when a disease is
eradicated, as has been the case of smallpox in the United
States, the risks of immunization may outweigh the possi—
ble gain. Specific immunization has not yet been success-
ful in many infections including the common cold.

In the future, the most dramatic examples of immuno-
logic augmentation will be perhaps in the field of cancer.
Immunologists believe that a patient is potentially capa-
ble of reacting against his own tumor. Why he does not
cure himself is not agreed upon. Some believe the immu-

129

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130

Table X: Immunosuppression

Immunosuppressive and Anti-inflammatory Agents

Cortisone, corticosteroids, and ACTH

Purine antagonists: azathiaprine (Imuran), 6-Mercaptopurine
Alkylating agents: cyclophosphamide (Cytoxan), nitrogen mustard
Folic acid antagonists: methotrexate

Antilymphocyte serum

Antihistamines (Benadryl, Actifed)

Conditions Frequently Treated With Anti-inflammatory and Immunosuppres—
sire Agents

Leukemias, lymphomas (Hodgkin’s disease)

Multiple myeloma

Rheumatoid arthritis

Asthma (severe)

Kidney transplants (and other organ transplants)
Ulcerative colitis

Nephritis (systemic lupus erythematosus and others)
Psoriasis

Childhood nephrosis

nity to be too weak to be effective, some believe there to be
an overload on the immune system through the release of
too much antigen by the tumor, while others believe in the
existence of blocking factors which inhibit the reactions of
lymphoid cells. Sought are means of removing blocking
factors, of increasing reactivity of the cells or of reducing
the antigenic load. In this area, numerous studies are al-
ready in progress, but success is completely unpredictable.
One novel possibility for manipulation is to re-examine
the homing of lymphoid cells in cancer patients. Studies
suggest that B cells precommitted to an immune response
rarely enter the peripheral circulation and that in patho-
logical states, precommitted T cells may sequester in
spleen or lymph node. A relatively simple manipulation
might induce more lymphoid cells to migrate to the tumor.
More orthodox are the proposals to increase the number
of committed cells by vaccination with tumor antigen or
with chemically modified antigen altered to render it more
immunogenic.

Cancer immunotherapy by augmentation is now chiefly
restricted to skin tumors, especially malignant melanoma
and multiple small cancers of the skin. In one mode of
treatment, a non-virulent form of tubercle bacillus is in-
jected; in the other, a delayed (Class IV) response is pro-

131

voked by painting the surface of the tumor with a dilute
solution of the sensitizing agent. Both have had spectacu-
lar success, but neither seems effective against tumors
located deep in the body.

c. Reconstitution. Reconstitution by transfer of immu-
nologically competent cells or cell products is a new and
exciting development in immunology and immunogenet—
ics. Restoration of immunity by the injection of antibody
or of lymphocytes has been attempted; both are fraught
with danger. Treatment of leukemia by the injection of
antibody has been attempted periodically since the 1920’s.
In the past, it has been less effective than conventional
x-ray or chemotherapy. However, potent antisera pro-
duced in monkeys are now becoming available. These sera
can be used in combination with other forms of therapy.

As mentioned in the section on transplantation, bone
marrow grafts can be successful in restoring full func-
tion. Unfortunately this occurs only in a very small pro-
portion of cases. Unless the bone marrow cells transferred
are antigenically identical with the donor, they will either
be rejected by the impaired but still functioning immune
system of the patient, or if immunity is further depressed
by anti-leukemic treatment, the graft may react against
and kill the patient.

Another form of reconstitution has been attempted only
in small scale trials. Experiments have shown that “trans-
fer factor,” an extract of the specifically sensitized lym-
phocytes of an immune individual, seems to have the
ability to convert non-immune lymphocytes of a patient to
immune lymphocytes. Such “transfer factor” has been
used with some success in treatment of leprosy, chronic
fungal infections of the skin, and possibly in some forms
of cancer.

Finally, just as passive treatment with serum has a
definite place in the treatment of certain patients at risk,
the transfer of mediators such as interferon, thymic hor-
mone and other substances may have a place in the short
term treatment of specific sub-classes of immunologic
deficiency.

132

The major remaining problems include the full recogni-
tion of existing opportunities, the allocation of resources
for the development of such new techniques, and the con-
tinuing need for additional basic information on the pre—
cise immunologic aberrations responsible for the many
and varied immune-related diseases of man.

B. Goals

1 . Cancer

A prime target of the immunologist is cancer. This tar—
get is one that, while still elusive, well fits the concept
“almost Within our grasp.” There are several immediate
immunologic goals.

Already practicable is the monitoring of patients for
recurrence of cancer. Such monitoring can now be done
for patients with tumors of the liver (hepatoma) and
with colonic cancer. Just as the hepatoma tumor releases
a-fetoprotein (AFP) and colonic cancer releases carcino-
embryonic antigen (CEA), many other tumor types of
cancer appear to release specific substances into the
bloodstream. Cancer of the ovary, uterus and cervix, and
skin melanoma appear to be among these diseases. As
soon as the appropriate antigen can be recognized, anti-
sera can be made and patients can be screened at regular
intervals after surgical removal of their tumors. A rising
level of antigen in the patient would constitute a warning
sign, recognizable by the physician as a possible recur-
rence.

Another possibility for immediate action is the moni—
toring of members of high-risk cancer families for onset
of the disease. Although not common in the general popu-
lation, familial polyposis occurs frequently in some fami-
lies, with as many as 50 percent of members developing
polyps. If undiagnosed and untreated, these polyps rap—
idly turn cancerous. The disease appears to be controlled
by a single dominant gene. Since most human chromo-
somes have now been mapped, it seems reasonable that
red and white cell typing could offer a ready means of

133

identifying which family members carry the trait. Those
members at risk would subsequently be given frequent
examinations, and would receive genetic counseling.
Members of such families would also be tested for rising
levels of carcino-embryonic antigen and positive results
would be considered an indication for possible interven-
tion.

A third, less immediate possibility, is the production of
a preventative cancer vaccine. It has recently been found
that viral antigens can be detected on the tumor cell even
when the virus itself cannot be demonstrated. This opens
up the challenging possibility that it may be unnecessary
to isolate the virus in order to prepare a vaccine. Using
existing technology it would be possible to isolate the anti-
genic fraction from tumor cell membranes grown in tissue
culture and thus to prepare a vaccine.

One long range objective of the immunologist is to
eliminate the need for cancer surgery. Under certain cir—
cumstances, it is possible for the immunological system of
a mouse to destroy a billion tumor cells in less than 48
hours. Indeed the more tumor cells present, the more ef-
ficient the destructive process becomes. A parallel exam—
ple in humans is the speed with which multiple warts on
the hands or feet vanish once one of them is successfully
attacked. The immunologist is hopeful that, in the same
manner, cancer that has already spread through the body
can be destroyed without surgery, without scarring and
without loss or damage to normal tissues or organs.

No one can share the intense frustration of the tumor
immunologist. He knows the immense power he can direct
against tumors in animals, but does not yet know how to
unlock this power in man. There are several possibilities
which may prevent such an eflficient immunological attack
from developing: (1) Blocking antibodies or antibody-
antigen complexes in serum prevent the lymphocyte from
attacking. (2) The patient with an antigenic tumor does
not have the appropriate immune response genes, i.e. he
lacks the genetic capacity to react against his own tumor
antigens. (3) The tumor liberates substances (e.g., vi-

134

ruses or enzymes) which interfere with the immunologi-
cal system. (4) The patient has made the wrong kind of
immune response, i.e. a humoral response instead of a
cellular response. (5) The patient may be unable to mo-
bilize his effector cells, so that they remain locked up or
sequestered in the lymphoid organs, never reaching the
cancer site. (6) The patient may be tolerant to the tumor
antigen.

There is experimental evidence to support each of these
possibilities. The suspicion must be entertained that each
of these factors is operating to a different degree; the
major deficiency in each case being due partly to features
of the particular tumor and partly to the genetic and en-
vironmental factors in the host. It is also possible that
immune responses can, augment rather than impede tumor
growth. The explosive growth of a Wilm’s tumor of the
kidney in a child is vastly different from the almost im-
perceptible progression of cancer of the bowel in the case
of the octogenarian. Indeed, the fulminant progress of
tumors in the young person lends strong credence to the
supposition that immune stimulation is operative at cer-
tain stages of life and promotes rather than prevents
tumor growth.

Despite these obvious differences between patients and
between tumors, there is a tendency to consider immuno-
logical factors in cancer as a single entity. This attitude is
surely destined to change dramatically in the future. The
physician of the future, diagnosing and treating a cancer
patient, is likely to request a full immunologic investiga-
tion including tests to detect and estimate the amount of
circulating antigen and of antibody, the proportion and
functional activity of each subpopulation of T and B
lymphocytes, and the pattern of migration of effector
cells. Other measurements he would request include the
characteristics of the patient’s immune response genes,
levels of thymic and other hormones, levels of each of the
complement components, and the functioning of the aux-
iliary immune apparatus including the ability to produce
interferon and the various lymphokines. The presence of

135

suppressor T cells, immuno-stimulatory cells and enhanc-
ing antibodies would be determined. Finally, an esti-
mate would be made of the potential of the patient’s
lymphocytes to respond to and kill his own tumor cells.
Treatment would be based on results from the evaluation
and on consultation with the immunologist, the pharma-
cologist and the surgeon. At present, the possibility of
such an extensive investigation for the many cancer pa-
tients remains a dream.

2. Transplantation

One: of the most fascinating achievements of immunol-
ogy, and, at the same time, by far the most tantalizing,
relates to the selection of donors for kidney or skin trans—
plantation. It is fascinating because in certain situations
the chance of restoring the patient to a normal vigorous
life is better than 90 percent. It is tantalizing because only
a small proportion of transplants fall within this category.

The problems of transplantation are great. First, the
functioning tissue has to be transferred in a living state.
This is the province of the surgeon, and, in general, the
technical problems have been solved. Once installed in the
body, the transplanted tissue is liable to attack from every
possible immune defense process. The cells making up the
transplanted tissue are not homogeneous. Some cells are
relatively resistant to attack, some are very sensitive to
antibody lysis and some are sensitive to attack by lym-
phocytes or macrophages. Graft destruction can follow
loss of blood supply through blood clotting or platelet ag-
gregation leading to death of vital cells within the
transplant. The task of the immunologist is to enable the
transplant to escape these varied processes by means
which do not jeopardize any of the normal functions of
other tissues or of the immunological defense. Failure to
protect the body leads to tumor induction, psychotic dis-
turbances, cosmetic defects and the many consequences of
infection, often with unusual pathogens. In the face of all
these problems the success already achieved in transplan-

136

tation of kidneys, heart and bone marrow is truly impres-
s1ve.

It is apparent from a variety of studies, human as well
as animal, that all tissues are not equally immunogenic.
Human tendons transplanted inside the intact tendon
sheath function for years with none of the inflammatory
reaction that follows the transplantation of bare tendon
without its fibrous sheath. Pig liver transplants survive
without immunosuppression whereas pig kidneys are
promptly rejected, ovarian transplants may over-ride the
immune response that rejects skin from the same donor.
There are many other examples. Similarly, some compo-
nents within a tissue may be more immunogenic than
others and the vascular endothelium and passenger lym-
phocytes in the tissues may be the prime triggers for the
immune response. Decreasing the immunogenic load by
perfusion of transplants with steroids and/or blocking
sera have been suggested as pre-treatments and these ap-
proaches offer some promise of success. Closer antigenic
matching, especially for those factors now being discov-
ered in the HLA histocompatibility complexes are an-
other promising approach. Selective unresponsiveness to
antigen from the kidney donor has been brilliantly sucess-
ful in the rodent.

One difficulty encountered in the introduction of po-
tential new treatments in man is that the established
procedures, i.e. dialysis and transplantation with immuno-
suppression, are reasonably successful, while treatments
not yet proven clinically are suspect. The few clinical re-
ports of the use of enhancing antibody in combination
with other therapy appear promising. Thus, immunologic
enhancement can be considered at least as an adjunct
therapy. The induction of immunologic tolerance to solu-
ble transplantation antigen has probably not been tried
in man. While it is difficult to see how tolerizing prepara-
tions could be tested ethically in unsensitized subjects, at-
tempts to solve the more difficult task of breaking known
immunity would be entirely ethical. Many patients have

137

been so presensitized by previous transfusions or trans-
plants that one can no longer find a donor not recognized
by their preformed antibodies. While inducing tolerance
or inhibiting antibody production might be extremely dif-
ficult, success would be of extreme value to these and many
other patients (including those with autoimmune dis-
eases).

The predictably successful transplants involve organs
or tissues which come from brothers or sisters who have
inherited exactly the same set of HLA genes from each
parent. Most siblings and parents differ by at least one
HLA set and in this type of transplant the immunologist
is working to distinguish between those kidneys that will
be well-accepted and those that will provoke a very strong,
and sometimes irreversible, immune response. In practi-
cal terms little obvious progress has been accomplished in
the past several years. However, in terms of background
knowledge and potential application, progress has been
impressive. Furthermore, in learning more about the im-
munogens important for transplantation, we are develop-
ing concepts that are relevant to cancer and to
autoimmunity.

Relevant new findings, which have aroused great opti-
mism that goals set can be reached, probably by several
alternative routes, include (1) awareness that the target
for cellular immunity is not necessarily the same as that
for antibody, (2) identification of genes linked to HLA
that control the production of these targets, (3) improved
definition of tissue types, (4) demonstration of immune
response genes in man, and (5) steadily expanding
knowledge of tolerance induction even in the face of exist-
ing immunity. In addition, an entirely new mechanism,
in which target cells are lysed by the interaction of anti-
body with normal or non—sensitized lymphocytes, has been
found. Studies on lymphocyte—antibody—lympholytic inter-
actions (LALI) are proceeding in several centers. A pre—
viously unknown antibody appears to be responsible for
this type of immunity. These recent discoveries are all
relevant to the solution of the complex problems of trans-

138

plantation. Indeed, one rather paradoxical asset from
basic research studies is that we now have a much clearer
understanding of the complexity involved in transplanta-
tion. Knowing the extent of the problem will help with the
solution.

One can conservatively predict that one or more of the
approaches outlined above will be successful within the
next ten years. What then will happen to transplanta-
tion? Initially, if the true success rate of kidney
transplantation with cadaveric organs, i.e. complete re-
habilitation within 3—6 months of the operation and con-
trol of the processes of rejection with only a minimal dose
of immunosuppressive drugs, approaches 80 percent,
there will be many thousands of kidney transplants per
year and a corresponding fall in money required for dialy-
sis. Secondly, forms of transplantation now rarely per-
formed, including heart, pancreas and liver, will become
commonplace. Finally, organs that are not now considered
transplantable, intestine, lung, uterus, esophagus, and
conceivably even limbs, may become practicable. This last
possibility arouses great compassion when one considers
the present state of some permanent inhabitants of Vet-
erans Administration hospitals. While not yet practicable
and certainly needing comparable advances in neurosur-
gery and neurophysiology, nevertheless, limb transplanta-
tion would be of inestimable value to countless young
persons.

3. Infectious diseases

The contribution of immunology in this area merits re-
statement. Without the protection afforded by modern
sanitation (water and sewer systems) and by vaccina-
tion, there would be no over-population problem, since
civilization as we know it could not exist. The social and
economic advantages to civilization from vaccination
against such major diseases as smallpox, diphtheria, po-
liomyelitis, tetanus, plague, cholera, and even the minor
ailments, measles, German measles, and whooping cough
are almost unimaginable. If a tiny proportion of the sav-

139

ings from poliomyelitis alone could be applied to further
research on immunity in infectious disease, many of the
remaining diseases could be overcome.

Due to the successes of modern medicine, the average
person in the U.S.A. does not expend much concern over
infection. However, tens of thousands are incapacitated
during influenza outbreaks, soldiers and school children
die of meningitis, and a present-day Oscar Wilde can still
contract syphillis.

One member of the general community not mentioned
extensively in this report, who is more conscious of the
dangers of contagion than most, is the’farmer. Vaccination
for avian leukosis has saved countless flocks of chickens
with the resultant economic saving to the farmer and the
consumer of poultry products. Hog cholera, a virus dis-
ease of swine, and swamp fever, a perennial threat to
horses and also due to a virus, are both controlled by vac—
cination. Unfortunately, foot-and—mouth disease of cattle
remains a constant threat, and a fully effective vaccine is
yet to be developed.

The military strategist probably also has an unusual
awareness of the threat of microbial infection. While
microbial warfare is outlawed, is there any absolute guar-
antee that it will never be used against the U.S.? While
the United States has no microbial offense, should it not
continue its studies on resistance to infection so that it
retains the potential to mount a flexible defense?

Many of the unconquered infections are chronic in na-
ture or cause only minor disability, so we tend to ignore
them. In truth, many of the costs of Medicaid, of hospital
insurance and the attendant loss of time from work or
school are solely due to common infectious diseases or to
infectious complications of other conditions. We have not
fully met our goal of protecting the people from infectious
disease and there is little prospect of doing so unless it is
realized that a continuing problem exists, one that costs
many millions of dollars a year in ineffective or even un-
desirable medicines, pain relievers, hospital or doctors
Visits and loss of productivity.

140

Following the precedent from other sections of this
chapter, let us see what progress can be foreseen. Most
immediately, progress could be made in several ways to
improve the effectiveness of vaccines. At present, some
organisms do not provide adequate immune stimulation
and others cannot be grown in culture. Since the genera-
tion of immunity is known to depend partly on the carrier
and partly on the hapten antigenic groups, new classes of
vaccine can be envisioned. As we learn more about the
composition of the antigen, synthetic vaccines could be
produced that would be effective and safe. Successful cul-
tivation of refractory organisms for the production of vac-
cines to hepatitis, syphilis, and the EB virus of some nasal
tumors requires continued painstaking effort, but success
is predictable. Use could be made of the known cross reac-
tions between the antigens of different microorganisms,
supplemented by a search for additional cross reactions,
thus permitting the stimulation of immunity to non-
pathogenic organisms which would also be effective
against pathogenic organisms. All of these steps are
straightforward, should be relatively inexpensive and
would pay immediate dividends. Such studies could also
provide new information about vaccine production that
could later be used in the preparation of anti—cancer vac—
cines.

In addition to such directly applicable approaches, we
need to learn more about the effects of infection on the
functioning of the immune system. Some viruses, such as
measles, are strongly suppressive of at least some immu-
nological responses. Other organisms, such as the obscure
C. parvum (related to organisms that cause diphtheria),
like the organisms causing pertussis and tuberculosis, can
stimulate the immune system. We need to know how they
act, what they can do and what other friends and foes re-
main unrecognized in our microbial flora. Since tumor
cells are apt to harbor viruses and since even bacteria be-
have differently when virus infected, these studies can
also add to our knowledge of tumor immunity or suscepti-
bility, and to our understanding of autoimmune diseases.

141

The preparation of vaccines, whether they be synthetic,
attached to a carrier, attenuated live organisms or strains
of organisms newly grown in tissue culture, is by itself
not enough. Some people are probably innately incapable
of responding to certain infections. Unless an individual
carries an appropriate set of immune response genes he
may be unable to recognize an invading organism. This
feature may explain why an organism such as the tubercle
bacillus was originally so lethal to many inhabitants of
the New World, While of lesser consequence to those of the
Old. The converse was true of the syphilis organism. The
mere recognition of the existence of such genes is very
new, and there is little detailed information even from
animal models. While a simple vaccine is adequate to pro-
tect one individual, another may need to have the antigen
presented in a different state for it to be recognized by his
immune response genes in order for it to be equally effec-
tive.

4. Autoimmunity

Autoimmunity probably presents the greatest chal-
lenge to immunology. The goals are very different from
those of cancer immunology, because instead of kindling
the reaction, the object is to extinguish it. However, it is
of immediate urgency to identify which of the many dis—
eases thought of as possibly autoimmune are, indeed,
primarily due to autoaggressive attack. We are reason-
ably certain that the clinical manifestations of glomerulo-
nephritis, rheumatoid arthritis, amyloid disease, post-viral
encephalitis, hemolytic anemias and immune thyroiditis
are of immunological origin. Many immunologists believe
that arteriosclerosis itself (and therefore many cases of
heart disease and stroke), some of the adverse effects of
aging, degenerative arthritis, multiple sclerosis, myasthe-
nia gravis, lupus erythematosus, and possibly even Hodg-
kin’s disease and leukemia should all be included in this
category.

Many of these diseases can be mimicked in experimen-
tal animals by injection of the appropriate antigen. Un-

142

like most human diseases, these animal experimental
conditions frequently do not progress. This leads to the
supposition that, in the natural disease, infection by a slow
virus maintains the antigenic challenge. The availability
of the New Zealand mouse, which has a high incidence of a
variety of autoimmune diseases, offers an excellent op-
portunity for analysis of the pathological processes.

The immunologist’s ultimate goal would be to identify
subjects at high risk and to prevent development of the
disease. This could be done most profitably, for example,
in individuals in whom there is a high correlation be-
tween a given HLA type and susceptibility to a disease.
Prevention could, in some instances, involve: (1) drug
therapy, (2) vaccination to minimize the risk of infection
With the inciting microorganism, (3) selective immuniza-
tion to induce the formation of protective blocking anti—
body, or possibly (4) induction or reinforcement of
tolerance. In the interim, confirmation that the disease is
autoimmune or that autoimmunity is responsible for its
progression is important information for the physician
since it will enable him to prescribe the most appropriate
treatment presently available. There is another substan-
tial gap in our knowledge requiring urgent attention. This
is how to arrest an established immune response. Filling
this gap would have an immediate and rewarding applica-
tion in autoimmunity as well as in transplantation and
in the treatment of allergies.

5. Allergy

Whereas one of the great difficulties with autoimmu—
nity is in identifying the diseases, this problem is minimal
or non-existent in the allergic diseases. Here, the prompt
response to allergen exposure (e.g. drug or pollen) pro-
vokes the reaction and thus confirms the diagnosis. In
allergy the objectives are to prevent (1) the formation of
reaginic (IgE) antibody, (2) the binding of antigen to
antibody on the mast cell surface, or (3) the release of
mediators from the mast cell. Present day drug therapy
(i.e. antihistamines, epinephrine) is mainly directed at

143

preventing the irritant effects of the mediators, while cur-
rent immunotherapy aims at desensitization. The results
of both leave much to be desired. Fundamental research
on how to erase immunologic memory is as needed in al-
lergy as in autoimmunity.

Fortunately, a number of‘ manipulations which can be
performed in experimental situations are expected to lead
to future clinical developments. Considerable advances
have been made in identifying the antigenically active site
of many antigens. With existing technology, it should be
possible to synthesize polypeptide antigens and to use
these, attached to carrier molecules, to induce tolerance.
Of great potential value is the finding that IgE regulation
is thymus-dependent and related to the level of IgG anti-
body. As IgG levels rise, IgE levels fall. Controlled im-
munization with insoluble hapten or antigen (possibly
with the aid of one of the new immunopotentiators), and
using radioimmunoassay monitoring of specific IgE anti-
body levels as a guide to effectiveness, is a potential de-
velopment.

Relatively undeveloped are the older observations that
menstruating females may lose hypersensitivity to skin
test allergens and that pregnant women may lose their
clinical symptoms of respiratory allergy. These effects do
not appear to be due to the hormones progesterone or
estrogen, but many opportunities exist for further studies
in this fascinating interface between immunology and
endocrinology. Finally, two other possibilities, both highly
speculative and with great implications for future devel-
opment, can be mentioned. One is the potential relation-
ship between allergy and transient neurological disorders
including, but not restricted to, migraine headaches. The
other is the potential use of aerosols and other locally ap-
plied antigens to effect local rather than systemic desen-
sitization.

6. General features

Immunology is a very vital and rapidly moving disci-
pline. What is only envisioned now will be reality within
a few years time, and mechanisms now unknown will then

144

begin to emerge. The full power of immunology When
properly harnessed to genetics and to biochemistry may
even be beyond the realm of our present vision.

Immunology is emerging as the central field of analysis
of communication between cells, thus elucidating the most
fundamental processes of normal cell regulation and its
aberrations. Since the system is so central to all bodily
functions, no estimate of its potential contribution to the
quality of life can possibly be projected. One needs only to
consider its potential for solution of the problems of aging
and of neoplastic disease.

C. Cost

Increasing knowledge of the importance of immune
mechanisms in human health and disease has made im-
munology a vital discipline. Man’s immune mechanism
constitutes both a blessing and a bane. It can be effective
against foreign invaders, and it can protect against a host
of diseases, through natural or acquired immunity. It can
sometimes be incompetent, inadequate, or unbalanced,
making man a victim of allergy. And it can tragically
lead to rejection of transplanted tissues or even, in auto-
immunity, to rejection of his own tissues.

Investigators exploring this burgeoning field of immu-
nology are indeed on a fantastic voyage, as startling and
innovative as the exploration of space. With the new tech-
niques for measuring cellular and humoral immunity,
there is indeed no limit to its further development.

What is the cost of such research? Throughout this re-
port, statements have been made to the effect that through
a given discovery, so many millions or billions of dollars
have been saved. Lives have been salvaged from diseases
that were untreatable or fatal for centuries, and the fear
and anxiety of many diseases have been erased. Immu-
nological research does contribute to the gross national
product, and Will no doubt contribute much more. The
eradication of Rh disease, using a treatment arising out
of basic immunologic research, is saving thousands of in-
fant lives, as well as millions of dollars each year. The

145

development of a measles vaccine resulted in new savings
of more than two million dollars in the state of Massa-
chusetts alone in 1965—71.

In addition, the development by immunologists of an
adenovirus vaccine to prevent acute respiratory disease in
military recruit populations has resulted in savings of
more than 7 million dollars in the relatively short time
that the vaccine has been in use.

A disease which is believed to be potentially amenable
to immunologic intervention and for whichcost estimates
are available, is rheumatoid arthritis. More than five mil-
lion people are affected by this disease; the majority of
the victims are between 20 and 45 years of age, hence
they represent the most productive segment of our popula-
tion. At an average cost of $800 per year per patient, the
annual cost to the nation in terms of lost wages and health
care costs exceeds 4 billion dollars. This exceeds the total
US. investment in research on this and all other diseases!

Impressive as these examples are, it should be kept in
mind that all medical progress is ultimately dependent on
new knowledge in basic, nonapplied research.

Biomedical research has two components, one applied
and one basic. Applied research can be and usually is
planned and targeted, just as though one were planning
to send a satellite to Mars. Attempts to target basic re-
search, though, are often counter-productive. As in cancer
research, the objective “prevent or cure cancer” can be
stated, but how this can be done cannot be programmed
in finite terms or known procedures. The early Virologists
could not set to work directly to produce polio vaccine.
They first had to learn how to cultivate tissue cells, then
they had to isolate the Virus and find out in which type
of cells the virus would grow adequately. Much basic re-
search which was not directed towards the specific goal of
making the vaccine was necessary. The outcome of this
research has saved an estimated two billion dollars each
year in direct medical and institutional costs and in time
otherwise lost from productive work. It has also provided
a basis for attempts to make other types of vaccine.

146

While the application of available knowledge can have
appreciable immediate effects, the continued support of
fundamental research is the only assured means for the
solution of these clinical problems that have vast social
and economic implications. Research is an indispensable
element of a country’s efforts to assure good medical care
and disease prevention, because upon such research de-
pends most of medical science’s present and future ability
to meet the challenge of the health needs of its people in
this rapidly changing world.

Support must be continuous. One of the consequences of
major scientific breakthroughs in the past has been the
immediate termination of funds rather than a switching
to related but unsolved problems. When antibiotics were
discovered, almost all research on the induction of immu-
nity to infection stopped. This was premature. Had sup-
port been continued, many of the infectious diseases that
still aifiict us could have already been conquered. When
Rh disease was eliminated, research stopped. There is pa-
thetically little investigation of another major attacker of
the newborn, antibodies to A and B blood groups. When
the cure for polio was announced, donations to the March
of Dimes fell precipitously and money that could have
been spent on cancer or other diseases was unavailable.
Discoveries such as those mentioned have saved the coun-
try countless billions. If some of the savings had been put
back into additional research, we might, for example, now
have some notable advances in the treatment of rheuma-
tism.

Medical research is expensive. It is wayward and often
appears to be unfocused. However, its benefits in the past
have been so great that it is not difficult to foresee that, if
continued at an adequate level, many revolutionary and
beneficial discoveries can be anticipated in the future. One
very simple precaution that can ensure continuity of re-
search is to incorporate into any major new health care
legislation a fixed portion to be used for research, just as
every major industry earmarks a proportion of its ex-
penditures for this purpose.

147

 

Appendix A
Immunology and Disease

GLOSSARY

acquired immunity—Immunity that develops as a result of exposure to a
foreign substance or organism.

adjuvant—A substance injected along with antigens which non—specifically
enhances or modifies the immune response to that antigen.

allergen—Any substance capable of eliciting an allergic response. Plant pol-
lens and animal danders are some of the most common allergens.

allergic response—One or more specific immune reactions which manifest
themselves in the form of a speCIfic allergic reaction.

allergic rhinitis—Inflammation occurring in the nasal passages of atopic
persons following contact with danders, pollens, or other airborne allergenic
substances.

allergy—A hypersensitive state acquired through exposure to a specific al-
lergen.

anaphylaxis—A reaction of the acute immediate hypersensitivity type which
follows the: administration of antigen into an immunuuhiegtr

antibody—A protein molecule produced-in the “body by lymphoid cells, particu-
larly plasma cells, in response to stimulation by antigen.

antigen—A substance that elicits a specific immune response when introduced
into the tissues of the body.

asthma—A chronic immune-related disease in which labored breathing and
Wheezing result from bronchospasm and excessive bronchial secretions.

atopy—A genetic tendency to develop sudden hypersensitivity states such
as allergic asthma or hay fever.

attenuated vaccine—A vaccine composed of living infectious organisms which
are of low Virulence. Such organisms stimulate active protective immunity;
however they are incapable of producmg serious disease.

autoantibody—An antibody appearing in an individual which reacts with
normal body constituents of that individual.

autoimmune disease—A disease resulting from an immune response against
antigens of an indiv1dual’s own tissues.

autoimmunity—Immunity to one’s own body constituents or tissues.

ECG—Bacillus Calmette-Guerin. A strain of the tuberculosis organism found
in cattle, now used as a living attenuated vaccine against the human
form of the disease.

blocking antibodies—(1) Incomplete antibody that may coat cells and prevent
them from clumping together or (2) antibody of one class that may com—

bine with the antigen ‘_and prevent itsfreacting with antibody of another
_class, thus preventingr allergic reactions for rejection of tissues.

blood groups—Antigens present at the surface of red blood cells which may
vary between individuals of the same species. The most important blood
groups in man are the ABO and the Rh blood groups.

bone marrow—Soft connective tissue located in the cavities of the bones.
bone marrow-derived cell—A lymphoid cell present in one of the lymphoid

149

organs which originated in the bone marrow and escaped the influence
of the thymus.

C—The abbreviation for serum complement.

C-reactive protein—A protein normally not present in serum but present
concomitant with many inflammatory processes. Although specifically
reactive with certain materials such as pneumococcal polysaccharides, it is
not an immunoglobulin molecule.

carrier protein—A protein to which a hapten has been conjugated thus con-
ferring upon the hapten the capacity to elicit spec1fic antibody.

cascade reaction—A progressive reaction such as that of the serum comple—
ment system in which reaction of the first component in the sequence
initiates the reaction of the next successive component, etc., until all com-
ponents of the system have reacted in fixed sequence.

cell-bound antibody—Any antibody bound to the surface of any cell.

cell-mediated immunity—Specific immunity which is mediated by small lym-
1 . 17”” -

phocytes and is dependent upon the presence of a thymus
cellular allergy—Allergy of the cell—mediated immunity type.
cellular immunity—Same as cell-mediated immunity.

clone—A family of cells derived from a single cellular ancestor and, there—
fore, genetically identical.

complement—A series of serum proteins which are. activated by antigen-
antibody reactions and which mediate important biological functions, such
as engulfment of particles by specialized cells.

cytotoxic antibody—Antibody which reacts with antigens present on a cell
surface and which produces damage to that cell or its surface.

delayed hypersensitivity——A cell~mediated immune reaction which normally
reaches its peak at about 24 hours after challenge.

determinant—A small site on an antigen with which a specific antibody may
react.

dialysis—1. The use of permeable membranes to separate substances of differ-
ing weights in solution. 2. A procedure used to “cleanse” the blood of pa-
tients with kidney failure.

drug allergy—A hypersensitivity reaction to certain drugs. Skin lesions
are frequent.

eczema—A skin._eruption common to atopic persons, with characteristic itch-
ing, inflammation and swelling.

erythroblastosis fetalis—The medical term for Rh incompatibility disease of
the newborn.

exchange transfusion—A technique by which the entire blood volume (usually
of an infant with erythroblastosis fetalis) is exchanged or replaced by
transfusion with appropriate donor blood.

food allergy—Allergy to components or constituents of food which may be
manifested by severe indigestion, diarrhea, vomiting or eczema.

globulin—A class of proteins characterized by being insoluble in water but
soluble in saline solutions.

glomerulonephritis—An autoimmune disease in which the major damage is
to the glomeruli of the kidney.

graft rejection—A cell-mediated immune reaction elicited by the grafting of
genetically dissimilar tissue onto a recipient. The reaction leads to destruc-
tion and ultimate rejection of the transplanted tissue.

graft-versus-host reaction—Disease which results upon transfer of lympho-
cytes from an individual who is genetically dissimilar to the recipient.

hapten—A substance that can combine with antibody but which can initiate an
immune response only if it is bound to a larger “carrier” molecule.

hay fever—A seasonal allergic disease causing inflammation of the eyes and
nasal passages.

150

heavy chain—A long chain of amino acids present in all immunoglobulin
molecules.

histamine—A chemical in the body that causes smooth muscle constriction
and dilation of the small blood vessels.

histocompatibility antigen—Genetically determined cell surface antigens.

HLA histocompatibility antigens—The cell surface histocompatibility anti-
gens on human cells which are important in tissue transplantation and
which are controlled by a single gene complex.

humoral antibody—Antibody which is present in the blood serum and tissue
fluid of the body and which is responsible for “humoral” immunity.

humoral immunity—Immunity mediated by s ecific antibodies which are pres-
ent in the blood serum and tis'siie‘ffii’ids’og the body.

hypersensitivity—-—The state, existing in a previously immunized individual,
in which tissue damage results from the immune reaction to a further
dose of antigen. If tissue damage is severe, the condition may be referred
to as one form of allergy.

Ig—See immunoglobulin.

IgA—The predominant immunoglobulin class present in body secretions such
as saliva, intestinal fluids, tears and bronchial secretions.

IgD—An immunoglobulin molecule present at very low concentrations in
human serum.

IgE—An immunoglobulin normally present at very low levels in man but
elevated in allergic diseases and in certain infections.

IgG—The predominant immunoglobulin class in human serum.
IgM—The high molecular weight immunoglobulin.
immune——Protected against disease.

immune response—The body’s response to a foreign substance.
immune tolerance—See immunological tolerance.

immunoassays—Immunologic methods using antigen-antibody reactions for
determining the concentration of antigens, antibodies or other biological
substances.

immunogen—A substance which on injection into the body can elicit an active
‘immune response. All immunogens are antigens, but not all antigens are
immunogens. I" ‘

immunoglobulin—Any globulin protein which is comprised of light and heavy
chains. All antibodies are immunoglobulins.

immunological rejection—Destruction of grafted foreign tissues or cells by
an immune reaction of the recipient.

immunological tolerance—Immunological unresponsiveness conferred upon an
indiv1dual by prior contact With a given antigen.

immunological unresponsiveness—The failure to manifest any demonstrable
immunologic response on encounter With an antigen.

immunologically competent cell—Any lymphoid cell capable of recognizing a
spec1fic antigen or mounting a specific reaction or response to an antigen.

immunosuppression—Suppression of immune responsiveness by external
agents, such as irradiation or drugs.

I.R.—Immune response.

killer cell—A thymus-derived lymphoid cell which, even in the absence of
complement, can destroy cells of a different type.

L chain—See light chain.
leucocyte—Any of the white cells of the blood.

light chain—A polypeptide of low molecular weight present on immuno—
globulin molecules.

151

lupus erythematosus—A fatal autoimmune disease, characterized by certain
antinuclear antibodies.

lymph nodes—Small pea-sized organs distributed widely throughout the body
which are composed mostly of lymphoid cells.

lymphocyte—A cell associated with all aspects of specific immunity. Lympho—
cytes are the chief constituents of lymphoid tissue.

lymphoid tissue—Body tissues in which the predominant cell type belongs to
the lymphoid series. This includes the spleen, lymph nodes, thymus, tonsils,
adenoids, and the circulating lymph.

macrophag(._Any of the diverse group of cells (except granulocytes) which
have the capacity to engulf and destroy foreign material.

mast cell—Tissue cells which play an imp01tant role in immediate hyper—
sensitivity reactions.

maternal immunity—Passive humoral immunity acquired by the fetus or
newborn infant by transfer of specific antibody from the mother.

memory cells—Lymphoid cells which, because of an earlier encounter with an
antigen, retain an increased reactivity to that antigen.

multiple myeloma—A form of cancer, characterized by the proliferation of
malignant cells in the bone marrow.

non-specific immunity—Bodily defense mechanisms which do not specifically
recognize antigens or mount specific immune responses, but which provide
for the destruction and removal of foreign substances.

phagocyte—A scavenger cell, such as a macrophage.

plasma cell—The predominant immunoglobulin-producing cell type of the
lymphoid cell series.

polypeptide—A chemical that yields amino acids when decomposed but which
is smaller than a protein.

prophylactic immunization—Immunization which prevents disease.

proteins—Complex chemical substances made up of amino acids; proteins
are essential constituents of all living cells.

radioimmunoassay—An immunologic procedure for measuring the concen-
tration of antigen or antibody by employing radioactively—labelled ma-
terials.

receptor—A chemical structure on the surface of any immunologically compe-
tent cell.

rejection—See immunological rejection.

Rh incompatibility—Incompatibility between certain blood group antigens of
a mother and her baby or between donor and recipient in blood transfusions.

rheumatic fever—An inflammatory disease of connective tissue involving
ma1n1y card1ac structures.

rheumatoid arthritis—A chronic inflammatory disease of the joints.

self-recognition—Recognition of self-antigens by one’s own immunologic sys-
tem.

sensitization—The injection of antigen so as to elicit an immune response.

serum (pl. sera)—The liquid part of the blood remaining after cells and
fibrin have been removed.

serum sickness—A disease, characterized by fever, joint swellings and en-
larged lymph nodes, which occurs in humans following repeated injection of
rather large quanti‘tigggfjpreign/antigens.

specific immunity—Immunity that results from the specific recognition of
antigens.

specificity—A term referring to the selective reaction which occurs between
an antigen and its corresponding antibody or lymphocyte.

spleen—An organ in the abdominal cavity, composed largely of lymphocytes
and macrophages. It is an important site of antibody production.

152

surveillance—The process by. which an intact immune system monitors both
self and foreign antigens.

T cell (T lymphocyte)—See thymus-derived cell.
thymocyte—Any lymphocyte residing in the thymus.

thymus—A central lymphoid organ of major importance in the development
of immune capability.

thymus-derived lymphocytes (T lymphocyte)—Small lymphocytes which on
(or after) residence in the thymus attain new immunologic capabilities.

tissue typing—The process of identifying and matching antigens on prospec—
tive donor and recipient tissues.

tolerance—See immunological tolerance.

toxoid—A chemically treated immunogenic exotoxin which can be used for
immunization since its toxicity has been largely removed or altered by
chemical treatment.

transfer factor—A cell-free substance from sensitized lymphocytes which can
transmit specific cellular immunity.

transplantation immunity—The immunity, largely cell-mediated, which de-
velops in a recipient following transplantation of donor tissues.

vaccination—The process of deliberately eliciting active immunity in an in-
dividual by administration of a vaccine or living antigen.

vaccine—An antigen-containing material of an organism which, on introduc-
tion into an individual, stimulates active immunity and future protection
against infection by that organism.

153

Appendix B
Task Force on Immunology and Disease

Description and Purpose

The history of medicine reveals many epochs, each of which elevated the
medical sciences to a new level of disease understanding, treatment, and pre—
vention, and in turn improved greatly the health status of the populace. The
period beginning in the 1950’s and since has contributed rapid development
of the field of immunology and revelation of the role of immunologic pro-
cesses in preventing, modifying or causing disease. In one way or another
immunology seems ,to be involved in almost every disease state.

The National Institute of Allergy and Infectious Diseases of the National
Institutes of Health has maintained through this development period a. major
program interest in support of immunologic research. Stemming from the
Institute’s program evaluation and advisory mechanisms was a realization
that a need existed to take stock of what is known about the relationship of
immunology to disease. For example: What are the immunologic diseases,
their incidence and prevalence, and what is their economic impact on the
public? What contributions has research in immunology made to a better
understanding of the disease process and to treatment and prevention? What
research results are ready for application at the clinical or preventive medi-
cine levels and how might this be accomplished? What are the promising
areas of immunologic research that warrant priority attention? To obtain
answers to these and other pertinent questions the Institute, with the advice
of the National Advisory Allergy and Infectious Diseases Council, decided to
sponsor the Task Force on Immunology and Disease.

The Task Force was initiated in July 1972 with a meeting of the Directing
Group, composed of the senior scientists and clinicians listed below. It was
decided that the most useful expenditure of efforts by this Task Force, and
the greatest value of the subsequent report, would be obtained through ad-
dressing the relationship of immunology and disease in the broadest terms.
It was felt that the information gathered and the recommendations developed
should be presented in a form useful to all interested persons, agencies, and
institutions and not limited to program interests of the National Institute
of Allergy and Infectious Diseases.

At this meeting, the broad field of immunology and disease was divided
into ten subheadings, each for detailed attention by a different Workshop
Panel. Panel chairmen were selected from the Directing Group and the
process of selecting Panel members was begun. Those individuals are listed
below as Participants. Individuals who made written contributions but did
not attend meetings of the Panels are listed as Contributors.

The Panel deliberations and preparation of reports occurred in three to
five meetings of each Panel. Each Panel produced two documents: a scientific
report and a summary report. The ten Panel reports were revised and amal-
gamated to form a single volume by the Editorial Group under the guidance
of the Task Force Chairman, Dr. D. Bernard Amos. The scientific report

154

exists as a separate publication entitled “Immunology and Disease.” The
summary report was rewritten in less technical language initially by a
science’writer, Mr. William Cole, and after further revisions is contained in
this volume.

The purpose of the Task Force has been to evaluate present knowledge on
immunology and its role in the cause, prevention, and treatment of disease.
This evaluation was to include the related health/cost impact and benefits;
identification of possibilities for clinical usefulness and the feasibility of rapid
achievement; and an indication of priority areas of research for increase of
needed knowledge and abilities. Last but not least, the goal included produc—
tion of reports that would convey this information in a meaningful way to
scientific and to nonscientific readers.

SPONSOR

NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
NATIONAL INSTITUTES OF HEALTH
Bethesda, Maryland 20014, U.S.A.

Dr. Dorland J. Davis, Director

Task Force General Chairman

Dr. D. Bernard Amos

Directing Group Members

Dr. D. Bernard Amos Dr. Irwin H. Lepow

Dr. K. Frank Austen Dr. Philip S. Norman
Dr. J. Werner Braun Dr. Philip Y. Paterson
Dr. Leighton E. Clufl' Dr. William E. Paul

Dr. Frank J. Dixon Dr. Fred S. Rosen

Dr. Frank W. Fitch Dr. Richard T. Smith
Dr. Charles A. Janeway Dr. John H. Vaughan
Dr. Samuel L. Kountz Dr. Byron H. Waksman

155

Dr

Dr.

Dr

Dr.
Dr.

Dr

D r

Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.

Dr

Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.

Dr.
Dr.
Dr.
Dr.
Dr.
Dr.
Dr.

Appendix C

Participants or Panel Members

. James C. Allen
Chester A. Alper
. D. Bernard Amos
K. Frank Austen
Fritz H. Bach

. Robert L. Baehner
Dr.
Dr.
Dr.

Allen E. Beer

J. Werner Braun
William B. Cherry

. Henry N. Claman
Leighton E. Clufl"
Charles G. Cochrane
John R. David
Frank J. Dixon
Alfred S. Evans
Frank W. Fitch
Edward C. Franklin
H. Hugh Fudenberg
. Robert A. Good
Edgar Haber

Karl E. Hellstrom
Ronald B. Herberman
Kimishige Ishizaka
Charles A. Janeway
Olga M. Jonasson
Samuel L. Kountz
Richard M. Krause
Saul Krugman
Henry J. Kunkel
Maurice Landy

H. Sherwood Lawrence
Edwin H. Lennette
Irwin H. Lepow

Robert Austrian
Marilyn L. Bach
Rudolf L. Baer
Benjamin A. Barnes
Rupert E. Billingham
Kurt J. Bloch

Barry R. Bloom

Dr. Bernard B. Levine
Dr. Lawrence M. Lichtenstein
Dr. Takashi Makinodan
Dr. Hugh 0. McDevitt
Dr. Donald L. Morton
Dr. Quentin N. Myrvik
Dr. Philip S. Norman
Dr. Charles W. Parker
Dr. Philip Y. Paterson
Dr. William E. Paul

Dr. Charles E. Reed

Dr. Fred S. Rosen

Dr. Richard Rosenfield
Dr. Elvio H. Sadun

Dr. George W. Santos
Dr. Matthew D. Scharfl"
Dr. Stuart F. Schlossman
Dr. Robert S. Schwartz
Dr. Gordon C. Sharp

Dr. N. Raphael Shulman
Dr. Richard T. Smith
Dr. Robert Stroud

Dr. Norman Talal

Dr. Emil Unanue

Dr. John H. Vaughan
Dr. Byron H. Waksman
Dr. Roy Walford, Jr.

Dr. Ralph C. Williams, Jr.
Dr. Darcy B. Wilson

Dr. Sheldon M. Wolff
Dr. Rosalyn Yalow

Dr. Edmond Yunis

Dr. Morris Zifl‘

Contributors

Dr
Dr
Dr
Dr
Dr
Dr
Dr

156

. Mortimer Bortin

. Carl Cohen

. Richard S. Farr

. Emil C. Gotschlich

. Leonard Greenberg

. William H. Hildemann
. Herbert E. Kaufman

in .-.. .

Dr. Edwin D. Kilbourne Dr. Jay P. Sanford

Dr. George B. Mackaness Mr. Joseph Schachter

Dr. Bruce Merchant Dr. Kenneth W. Sell

Dr. Joseph E. Murray Dr. Arthur M. Silverstein

Dr. Leslie C. Norins Dr. Daniel J. Stechschulte
Dr. Louis J. Olivier Dr. Jonathan W. Uhr

Dr. Roy Patterson Dr. Thomas E. Van Metre, Jr.
Dr. G. Nicholas Rogentine, Jr. Dr. William O. Weigle

Dr. Donald A. Rowley

Editorial Group

Dr. D. Bernard Amos Dr. Janet Plate
Dr. Geoffrey Haughmn Dr. D. Rowlands
:_ Dr. A. H. Johnson Dr. David W. Scott
:35» Dr. A. s. Kemp Dr. Wade K. Smith
. Dr. Nelson Levy Dr. Ralph Snyderman
7“ Dr. Eugene Ornellas Dr. Karen Sullivan
‘ Dr. Joy Palm Dr. Frances E. Ward

Revision of Summary Report Only

i3?- Earl C. Chamberlayne Margaret G. McElwain
J. Latham Claflin Philip R. B. McMaster
‘ William Cole Bruce Merchant
‘ David H. Davis Gwen H. Northcutt
“1:; Albert A. Gam James D. Owens
Kay Hiemstra George E. Presson
David B. Keister Robert L. Schreiber
Donna Kostyu Julianne Williams

Walter H. Magruder

Task Force Secretariat

Dr. E. C. Chamberlayne
Dr. Bruce Merchant
Dr. Alfred M. Webb

 

 

157

Q U.S. GOVERNMENT PRINTING OFFICE: 1976 0—587-754

 

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U.S. DEPARTMENT OF HEALTH, EDUCATION, AND WELFARE

Public Health Service
National Institutes of Health

DHEW Publication No. (NIH) 75-940