Immunologic Defects in Laboratory Animals 1

364 Pages·1981·8.524 MB·English

by  R. B. Ashman (auth.), M. Eric Gershwin, Bruce Merchant (eds.)

Immunologic
1
Defects in
Laboratory Animals
Immunologic
Defects in
1
Laboratory Animals
Edited by
M. Eric Gershwin
University of California School of Medicine
Davis, California
and
Bruce Merchant
Food and Drug Administration
Betherda, Maryland
PLENUM PRESS. NEW YORK AND LONDON
Library ofCong~5S Cataloging in Publication Data
Main entry und~r titl~:
Immunologic defe<:1$ in laboratory animal~.
Indud~~ ind~x.
I. Immunological ddici~ncy syndromes. 2. Laboratory animals. 3. Mice as
laboratory animals. I. Gershwin, M. Eric, 1946- H. Merchant, Bruce.
QRI88.3S.l47 616.07'9 80-28192
ISBN 978-1-4757-0327-6 ISBN 978-1-4757-0325-2 (eBook)
00110.1007/978-1-4757-0325-2
© 1981 Plenum Press, New York
Sllftco'·er reprint of the hardcover 1st edition 1981
A Division of Plenum Publishing Corporation
233 Spring StrT«t, New York. N. Y. 10013
All rights r~so:rved
No part of this book may be reproduced, stored in a retrieval system, Or transmitted,
in any form or by any means, electronic. mechanical, photocopying, microfilming,
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Contributors
HANS ABPLANALP, Department of Avian Sciences, University of California, Davis, California
95616
AFTAB AHMED, Department of Immunology, Merck Institute for Therapeutic Research, Rahway,
New jersey 07065
R. B. ASHMAN, Department of Microbiology, john Curtin School of Medical Research, Australian
National University, Canberra, Australian Capital Territory 2601, Australia
JACK R. BATTISTO, Department of Immunology, Research Division, Cleveland Clinic Foundation,
Cleveland, Ohio 44106
ALBERT A. BENEDICT, Department of Microbiology, University of Hawaii, Honolulu, Hawaii
96822
GUIDO BIOZZI, U 125 INSERM and ER 70 CNRS, Immunogenetic Service, Curie Institute,
Biology Section, 75231 Paris Cedex 05, France
E. J. BRANDT, Corporate Research Laboratories, Monsanto Company, St. Louis, Missouri 63166
DAVID C. DALE, Department of Medicine, School of Medicine, University of Washington, Seattle,
Washington 98195
RENE J. DUQUESNOY, Blood Center of Southeastern Wisconsin and Department of Microbiology,
Medical College of Wisconsin, Milwaukee, Wisconsin 53201
KENT L. ERICKSON, Department of Human Anatomy, School of Medicine, University of Califor
nia, Davis, California 95616
MICHAEL F. W. FESTING, Medical Research Council Laboratory Animals Centre, Carshalton,
Surrey SM5 4EF, England
M. ERIC GERSHWIN, Section of Rheumatology-Clinical Immunology, School of Medicine, Univer
sity of California, Davis, California 95616
WILLIAM P. HAMMOND, Department of Medicine, School of Medicine, University of Washington,
Seattle, Washington 98195
BERENICE KINDRED, German Cancer Research Center, D-6900 Heidelberg, West Germany. Pres
ent address: Max Planck Institute for Biology, Immunogenetics Section, Tiibingen, West
Germany
v
VI CONTRIBUTORS
DENISE MOUTON, U 125 INSERM and ER 70 CNRS, Immunogenetic Service, Curie Institute,
Biology Section, 75231 Paris Cedex OS, France
E. K. NOVAK, Molecular Biology Department, Roswell Park Memorial Institute, Buffalo, New
York 14263
JOHN 1. O'DONOGHUE, Toxicology Section, Health, Safety, and Human Factors Laboratory, East
man Kodak Company, Rochester, New York 14650
GRETE M. PEDERSEN, Blood Center of Southeastern Wisconsin and Department of Microbiology,
Medical College of Wisconsin, Milwaukee, Wisconsin 53201
CAROLYN REED, Department of Laboratory Animal Medicine, University of Rochester Medical
Center, Rochester, New York 14642
DAVID 1. ROSENSTREICH, Department of Microbiology, Albert Einstein College of Medicine,
Bronx, New York 10461
IRWIN SCHER, Naval Medical Research Institute and the Uniformed Services University of the
Health Services, Bethesda, Maryland 20016
J
SAUL SHARKIS, Oncology Center, The Johns Hopkins University School of Medicine, Baltimore,
Maryland 21205
REGINA R. SKELLY, Laboratory of Vision Research, National Eye Institute, Bethesda, Maryland
20205
CLAUDE STIFFEL, U 125 INSERM and ER 70 CNRS, Immunogenetic Service, Curie Institute,
Biology Section, 75231 Paris Cedex OS, France
R. T. SWANK, Molecular Biology Department, Roswell Park Memorial Institute, Buffalo, New
York 14263
STEFAN IE N. VOGEL, Laboratory of Microbiology and Immunology, National Institute of Dental
Research, National Institutes of Health, Bethesda, Maryland 20205
WANDA LIZAK WELLES, Department of Immunology, Research Division, Cleveland Clinic Foun
dation, Cleveland, Ohio 44106. Present address: Kidney Disease Institute, New York State
Department of Health, Albany, New York 12201
ANITA CORMAN WEINBLATT, Laboratory of Microbiology and Immunology, National Institute of
Dental Research, National Institutes of Health, Bethesda, Maryland 20205
WIESLAW WIKTOR-]EDRZEJCZAK, Laboratory of Radiation Immunohematology, Military School
of Medicine, Warsaw, Poland
Preface
Tiselius demonstrated that the immunologically active components of immune sera
migrated electrophoretically in the gamma globulin region. His findings illuminated the
classic observations of Jenner regarding development of resistance to infection, and those
of von Pirquet, Pasteur, and Arthus regarding the transfer and specificity of resistance.
Conceptual integration of these observations provided the impetus for the present modern
era of immunology. Subsequent to Tiselius's work, multiple, rapid advances have occurred
in the study of congenital and acquired immune deficiency states in mice, chickens, and
humans. These studies have readily demonstrated that the immunologic ability of an organ
ism to protect itself from environmental influences is a prerequisite for survival. Indeed,
this necessity for protection from microenvironmental influences has promoted the evolu
tionary development of immunologic diversification, namely, host dependence upon a
sophisticated, multifaceted network of cells and effector mechanisms responsible for the
clearance and neutralization of toxins and potentially harmful pathogens. The obligate
dependence of animals upon the functional integrity of their immunologic systems is illus
trated by the ready invasion of ubiquitous organisms when the host is in a state of immune
defense derangement. Nevertheless, derangements in immune function can range from par
tial to complete and can be compatible with survival. The consequences of such derange
ments run the gamut from subclinical disease to inevitable mortality.
To further our understanding of such events, investigators have concentrated on the
study and manipulation of a number of spontaneously occurring animal models that have
genetically associated immune defects. Although direct extrapolation of data from animal
to man must proceed with caution, the use of such immunodeficient animal systems, both
in vitro and in vivo, has been an enormous help in the development of immunologic
concepts.
Our intention in preparing these books was to place between covers a functionally
rather than taxonomically organized exposition of the major immunologic defects as they
occur in laboratory animals. We hope that this effort will be of service to the scientific
community and that it will stimulate further investigations of immunologic defects. This
work was not intended to be exhaustive, but rather illustrative of the better-studied immune
defects and of the diverse and interrelated categories that they manifest.
There has been a rapidly accelerating recognition of immune defects in recent years.
Vll
Vlll PREFACE
This accelerating recognition of immune defects, especially in laboratory mice, leads us to
believe that we have only begun to identify the many forms of immune defects that may
take place. Given sufficient time, every possible immune defect should ultimately occur.
Eventually, immunologists may well identify and characterize a myriad of immune defects
representative of each successive biochemical step in each separate component of the com
plex immune system.
Despite our limited current knowledge of the extent and variation of immune defi
ciencies, defects in species as diverse as horses, mink, dogs, guinea pigs, rats, and chickens
are represented within this work. In addition, pigs, sheep, and quokkas have been given
additional attention for pecularities expressed by their immune systems either for reasons
of unique environment or because of unique ontologic development. Nonetheless these
books deal predominantly with immune defects as recognized in various strains of labora
tory mice. They generally concentrate on those defects already subjected to some systematic
studies and thus reflect the vagaries of contemporary inquiry. Immune defects in mice have
received much attention, but many other species have been relatively neglected. If dogs, for
example, were all tiny animals with very short gestation periods and were available as
highly inbred strains, it is quite possible that they might represent the most convenient and
preferred laboratory animal and thus be the species in which we would have our greatest
knowledge of immune defects.
Any functional treatment of immune defects in laboratory animals might be expected
to concentrate not only on reasonably distinct T-cell, B-cell, macrophage, and hematologic
defects, but also on complex, less well-defined defects which, for example, could be mani
fested in the form of autoimmune diseases. In this respect, our work is no exception. We
have also provided chapters, however, devoted to examination of the immune system under
unique environmental circumstances as, for example, with the evaluation of immunity in
germfree animals and with the analysis of immune potential during very early ontogenetic
development.
Generally, the various sections and chapters of this book are devoted to comparisons
between animals bearing genetically determined immune defects and normal animals of the
same species. Except for an effort to compare animal immune defects with their relatively
obvious counterparts in human clinical syndromes, comparison between species has been
largely neglected. This has been intentional partly because of the recognized dangers of
such extrapolation. The lack of comparison between species has also been due to the con
ceptual difficulties inherent in such comparisons. Nonetheless, one day we would hope to
comprehend why whole species may lack some generally recognized immune capability
that is ordinarily accepted as essential to survival in other species. For instance, the capacity
to mount active humoral immune responses to soluble polysaccharide antigens is recognized
as having distinct survival advantages both in humans and in mice, yet no one has acquired
sufficient immunologic insight to explain why the total failure to perform this "essential"
immune function does not seem to place rabbits, as a species, at any great evolutionary
disadvantage.
Immune defects have often been referred to as experiments of nature, and it is appar
ent that these experiments often diminish the survival capacity of the individual. However,
those complex immune defects that promote autoimmune disease with aging seem to exert
little evolutionary pressure if most defective animals have already reached reproductive
maturity prior to clinical expression of their autoimmune syndrome. On the other hand,
some immune defects may represent experiments of nature that actually succeed. Mutative
PREFACE IX
loss of an immune function that is no longer relevant to the environment of a given species
may actually represent a merciful excision of excess genetic baggage. Some such immune
defects may be critical experiments of nature that actually function to enhance alternative
immune adaptations.
Although a primary objective of this work was to promote unification of our concepts
of the immune system, on reflection one of its more essential messages may well be that the
immune system still escapes full definition. Rather than representing a monolithic system
imposed on many related species it probably represents a polylithic system, components of
which have been selected and amplified in those species that found them most useful. There
may well be numerous different immunologic solutions to similar evolutionary problems.
As an example of such thinking, evidence is presented herein that suggests the existence,
beyond B cells and T cells, of a third specific immune recognition system-possibly sub
served by nonlymphoid cells-which has evolved in marsupial species such as the quokka.
This evidence certainly invokes the question of whether such a system has been retained in
most other mammals. If such a third specific recognition system exists in humans, it might
well account for some examples of chronic graft rejection that appear refractory to all
known efforts at immunosuppression.
When one considers that defects of any and all features of the immune system are
ultimately probable, it is rather astounding that certain types of mutations have led to
immune defects that have been so constrained in their expression. At least five separate
mutations in three separate rodent species have resulted in thymic agenesis with coexistent
lack of hair follicle development. Although minor phenotypic differences certainly exist
between these mutations, they are each characterized by the loss of multiple parameters of
T -cell function, such that their similarities are much more notable than their differences.
When compared with osteopetrotic mutations, which are markedly diverse in character, or
with the multiple beigelike mutations of rodents, the various mutations that produce athy
mia are notably constrained in their overall phenotypic expression. Does this indicate that
certain stretches of genomic information that code for thymic development are especially
prone to mutative change? And does it indicate that thymic development is invariably
associated with development of the integument and its adnexae? Might the converse be
true? To the best of our knowledge there has been no concerted or systematic effort aimed
at identifying rodents with excessive hair development or in testing them for possible robust
or excessive T-cell function.
The immune system has evolved almost certainly as a host adaptation aimed at meet
ing the demands of self recognition for hosts that must exist in a sea of microorganisms.
But defense against microorganisms has not been the only consequence of immune system
evolution. A unique commensal association has developed between the immune system and
these microorganisms, since the immune system depends to a great extent for its own devel
opment upon the microbial flora of its natural environment. The immune systems of ani
mals raised in the absence of microbial flora or their products are incompletely developed
and, for all practical purposes, defective in expression of their genotypic capacities. T-cell
functions appear to be much less essential in axenic than in conventional animals. Indeed,
if thymic ablation experiments had been conducted only under germfree conditions, our
current concepts of T-cell function would, in all likelihood, not have been deduced. Thus
our appreciation of immune defects may often be relative and dependent upon the environ
ment in which investigations of such possible defects are conducted.
Although these books concentrate heavily on genetic, anatomic, pathologic, and func-
x PREFACE
tional definitions of immune defects and on their conceptual and theoretical relationships,
they also contain information aimed at coping practically with the study of immune dis
orders. Notable in this practical emphasis is the chapter on freezing of mammalian
embryos. This sophisticated approach to genetic conservation should allow development of
repositories of mouse embryos harboring one or more immunologic defects. The logistical
aid that can be provided by this new approach is considerable for both immunologic and
genetic studies. In the future, it seems likely that many rare, diverse, and exotic immune
defects of laboratory animals may well be retained and protected from inadvertent loss by
the use of this powerful technology. If we have indeed only scratched the surface in our
detection, recognition, and characterization of immune defects, then capabilities such as
mammalian embryo freezing will in all probability be instrumental to our future capability
to categorize and characterize the many potential defects of the immune system.
Finally, this preface would not be complete without significant appreciation expressed
to Jody Wall and Jeanie Redding for their untiring assistance.
M.E.G.
B.M.
Davis and Bethesda
Contents
Contents of Volume 2 .. xix
PART I. DEFECTS OF IMMUNE MATURATION
Immunologic Unresponsiveness in Fetal and Neonatal Mammals: A Paradigm for
Immune Deficiency Diseases?
R. B. ASHMAN
1. Introduction. . .......................... . 3
2. The Thymus and Lymphatic System. . .......... . 4
3. Ontogeny of Immunocompetence .......................................... . 5
3.1. Humoral Responses . . . . . . . . . . . . . . . . ........ . 6
3.2. Cellular Responses .................... . 7
4. The Effect of Thymectomy on Immune Responsiveness . . . . . . . . . . . . ......... . 8
4.1. Growth and Development ............................................ . 8
4.2. Circulating Lymphocytes .................................... . 8
4.3. Lymphoid Tissues. . . . . . . . . . . . ................. . 8
4.4. Antibody Responses .................. . 9
4.5. Transplantation Immunity. ........ . . . . . . . . . . . . . . . . ...... . 9
4.6. Delayed Hypersensitivity. . ........................................ . 10
4.7. Lymphocyte Transfer Reaction ....................................... . 10
4.8. Response to Polyclonal Mitogens ...................................... . 10
4.9. Life Span. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...... . 11
5. The Immunologic Function of the Thymus. . .................. . 11
6. Conclusions . . . . . . . . . . . . . . . . . . . . .. . ................. . 13
References. 13
Xl