Immunological Tolerance. Mechanisms and Potential Therapeutic Applications

618 Pages·1974·31.061 MB·English

by  David H. Katz, Baruj Benacerraf

ACADEMIC PRESS RAPID MANUSCRIPT REPRODUCTION
Proceedings of an International Conference Held at
Brook Lodge, Augusta, Michigan
April 27 -May 1, 1974
IMMUNOLOGICAL
TOLERANCE
MECHANISMS AND
POTENTIAL
THERAPEUTIC
APPLICATIONS
Edited by
DAVID H. KATZ, M.D.
BARUJ BENACERRAF, M.D.
Department of Pathology
Harvard Medical School
Boston, Massachusetts
ACADEMIC PRESS New York San Francisco London
A Subsidiary of Harcourt Brace Jovanovich, Publishers
COPYRIGHT © 1974, BY ACADEMIC PRESS, INC.
ALL RIGHTS RESERVED.
NO PART OF THIS PUBLICATION MAY BE REPRODUCED OR
TRANSMITTED IN ANY FORM OR BY ANY MEANS, ELECTRONIC
OR MECHANICAL, INCLUDING PHOTOCOPY, RECORDING, OR ANY
INFORMATION STORAGE AND RETRIEVAL SYSTEM, WITHOUT
PERMISSION IN WRITING FROM THE PUBLISHER.
ACADEMIC PRESS, INC.
Ill Fifth Avenue, New York, New York 10003
United Kingdom Edition published by
ACADEMIC PRESS, INC. (LONDON) LTD.
24/28 Oval Road, London NW1
Library of Congress Cataloging in Publication Data
Main entry under title:
Immunological tolerance.
Proceedings of an international conference held at
Brook Lodge, Augusta, Mich., Apr. 27-May 1, 1974.
Bibliography: p.
1. Immunological tolerance-Congresses. 2. Immuno-
therapy-Congresses. 3. Immunosuppressive agents-
Congresses. I. Katz, David H., ed. II. Benacerraf,
Baruj, Date ed. [DNLM: 1. Immune tolerance-
Congresses. QW504I361 1974]
RM276.I45 615'.36 74-16469
ISBN 0-12-401650-2
PRINTED IN THE UNITED STATES OF AMERICA
PARTICIPANTS
Dr. Gordon Ada Dr. Antony Basten
John Curtin School of Medical Department of Bacteriology
Research Immunology Unit
Australian National University The University of Sydney
Canberra, A.C.T., 2600 Sydney, N.S.W. 2006
Australia Australia
Professor Baruj Benacerraf
Department of Pathology
Dr. Anthony C. Allison Harvard Medical School
Clinical Research Centre 25 Shattuck Street
Watford Road, Harrow Boston, Mass. 02115
Middlesex HAI, 3UJ
Dr. Yves Borel
England
Department of Medicine
Tufts University School of
Medicine
Dr. Richard Asofsky
Boston, Mass. 02111
Laboratory of Microbial Immunity
National Institute of Allergy and
Dr. Sven Britton
Infectious Diseases
Division of Immunobiology
National Institutes of Health
Karolinska Institute
Bethesda, Maryland 20014
Wallenberg Laboratory
104 05 Stockholm 50
Sweden
Dr. Michael K. Bach
Hypersensitivity Diseases Research Sir Macfarlane Burnet
The Upjohn Company Department of Microbiology
Kalamazoo, Michigan 49001 University of Melbourne
Parkville 3052
Victoria, Australia
Dr. Phillip Baker
Laboratory of Microbial Immunity Dr. Jacques S|iiller
National Institute of Allergy and Scripps Clinic and Research
Infectious Diseases Foundation
National Institutes of Health 476 Prospect Street
Bethesda, Maryland 20014 La Jolla, California 92037
IX
PARTICIPANTS
Dr. Bernhard Cinader Dr. Karl-Erik Hellström
Department of Medical Cell Department of Pathology
Biology University of Washington
University of Toronto Seattle, Washington 98195
Toronto 181, Ontario
Canada
Dr. Leonore A. Herzenberg
Dr. Henry Claman Department of Genetics
Department of Medicine Stanford University School of
University of Colorado Medical Medicine
Stanford, California 94305
Center
4200 East Ninth Avenue
Denver, Colorado 80220 Dr. James G. Howard
The Wellcome Research
Dr. Sheldon G. Cohen, Chief Laboratories
Allergy and Immunology Branch Langley Court
Extramural Programs Beckenham
National Institute of Allergy and Kent BR3 3BS, England
Infectious Diseases
National Institutes of Health
Dr. John H. Humphrey
Bethesda, Maryland 20014
National Institute for Medical
Dr. Erwin Diener Research
MRC Transplantation Unit The Ridgeway, Mill Hill
London, NW7 1AA, England
University of Alberta
Edmonton, Alberta
Canada Dr. David H. Katz
Department of Pathology
Dr. David Dresser
Harvard Medical School
National Institute for Medical
25 Shattuck Street
Research
Boston, Mass. 02115
The Ridgeway, Mill Hill
London NW7 1AA
England Dr. Sidney Leskowitz
Department of Pathology
Dr. Marc Feldmann
Tufts University School of
Department of Zoology
Medicine
University College London
Boston, Mass. 02111
Gower Street
London WCIE 6 BT
England Dr. Rose Mage
Laboratory of Immunology
Dr. Richard K. Gershon National Institutes of Allergy and
Department of Pathology Infectious Diseases
Yale Medical School National Institutes of Health
New Haven, Connecticut 06510 Bethesda, Maryland 20014
x
PARTICIPANTS
Professor Hugh O. McDevitt Dr. Gregory W. Siskind
Department of Medicine Department of Medicine
Stanford University School of Cornell University Medical School
Medicine New York, New York 10021
Palo Alto, California 94304
Dr. Richard T. Smith
Dr. Graham Mitchell Department of Pathology
The Walter and Eliza Hall University of Florida Medical
Institute of Medical Research School
Royal Melbourne Hospital Gainesville, Florida 32601
Victoria 3050, Australia
Dr. Tomio Tada
Department of Pathology
Dr. Erna Möller
School of Medicine
Division of Immunobiology
Chiba University
Karolinska Institute
Chiba, Japan
Wallenberg Laboratory
104 05 Stockholm 50
Dr. R. B. Taylor
Sweden
Department of Pathology
University Medical School
Dr. Göran Möller
University Walk
Division of Immunobiology
Bristol, BS8 1TD
Karolinska Institute
England
Wallenberg Laboratory
104 05 Stockholm 50
Dr. William Terry
Sweden National Cancer Institute
National Institutes of Health
Bethesda, Maryland 20014
Professor G. J. V. Nossal
The Walter and Eliza Hall
Institute of Medical Research Dr. Emil R. Unanue
Royal Melbourne Hospital Department of Pathology
Victoria 3050, Australia Harvard Medical School
25 Shattuck Street
Dr. William E. Paul Boston, Mass. 02115
Laboratory of Immunology
National Institutes of Allergy and Dr. Byron Waksman
Infectious Diseases Department of Microbiology
National Institutes of Health Yale Medical School
Bethesda, Maryland 20014 New Haven, Connecticut 06510
Dr. David W. Scott Dr. William O. Weigle
Department of Microbiology and Scripps Clinic and Research
Immunology Foundation
Duke University Medical Center 476 Prospect Street
Durham, North Carolina 27710 La Jolla, California 92037
XI
PREFACE
Immunological tolerance has stimulated the curiosity of immunologists
for decades in a highly teleological sense, because, on the one hand, it is well
understood that it is nature's provision to allow the complex mammalian
organism to coexist within itself, and, on the other hand, although the
phenomena have been reasonably well defined, the cellular and molecular
mechanisms underlying them remain largely enigmatic.
The contents of this book represent the proceedings of a conference held
at Brook Lodge, Michigan, April 27-May 1, 1974, at which time we were
privileged to bring together many of the investigators who have actively
contributed to furthering our knowledge and understanding of immunolog-
ical tolerance. It will be immediately clear to the reader that the conference
was structured in a way to consider phenomena of tolerance and immune
suppression as interrelated entities with a certain degree of emphasis on the
possible common cellular mechanisms involved. The results of the confer-
ence do not make the cellular and molecular mechanisms underlying toler-
ance and suppression any less enigmatic, but, rather, do place a realistic and
sharp perspective on where we must focus our subsequent investigative
energies in order to answer the unresolved questions. Perhaps more impor-
tant is the fact that, as will be apparent to the reader, we have now reached the
stage at which our laboratory models have become sufficiently well under-
stood to permit us to consider seriously the clinical applicability of our
rapidly advancing technology in this area.
The recognition of the role of the thymus-derived or T lymphocyte as a
regulatory cell for immune responses endowed with the capacity to both
facilitate and suppress the functions of other T lymphocytes and bone
marrow-derived B lymphocytes in reactions of cell-mediated and humoral
immunity has clearly deepened our understanding of the control
mechanisms involved in these responses. However, we are now faced with
the increasing complexity that this understanding places on the concept of
specific immunological tolerance. It is, indeed, a more realistic concept that
we are forced to recognize and deal with and certainly in keeping with
evolutionary trends to diverge from the simple to the more highly integrated
system as the ladder extends further up the tree. We can no longer justify the
xiii
PREFACE
simpler connotation of immunological tolerance as the deletion of specific
clones of immunocompetent lymphocytes due to mechanisms unknown, for
while such clonal deletion probably does, in fact, occur under certain circum-
stances, the existence of other pathways to the same functional end—namely,
specific unresponsiveness—can be demonstrated experimentally and proba-
bly also plays an important physiologic role in the induction and/or mainte-
nance of tolerance. The role of suppressor T cells is particularly important,
as it is pointed out in these proceedings, as an alternate pathway to specific
unresponsiveness in populations of both T and B lymphocytes, and we are
left with the general impression that the origin and maintenance of self-
tolerance, perhaps the most enigmatic of all questions, reflects the operation
of both clonal deletion and suppressor T cell mechanisms. The precise
nature of these mechanisms will hopefully be delineated to a greater extent
by the time of the next tolerance conference.
In closing, we wish to acknowledge the outstanding efforts of Ms. Candace
H. Maher in the organization and planning of this conference. Mrs. Annette
Benacerraf for her secretarial assistance during the conference and Ms.
Deborah Maher for her tireless work in the preparation of this book. This
conference was made possible by the support of the National Institute of
Allergy and Infectious Diseases, the National Institutes of Health, and the
Upjohn Company, which also made available to us the luxurious and serene
setting of Brook Lodge.
David H. Katz
Baruj Benacerraf
XIV
Leonore A. Herzenberg Richard K. Gershon Jacques M. Chiller Erna Möller Baruj Benacerraf Professor G, J. V. Nossal
Michael K. Bach Baruj Benacerraf
Conference In Session
Sir MacFarlane Burnet
Dr. Graham F. Mitchell
FACTORS INFLUENCING THE RATE OF INDUCTION
OF TOLERANCE BY BOVINE GAMMA GLOBULIN
D.W. Dresser
National Institute for Medical Research
Mill Hill, London NW7 1AA
INTRODUCTION
Antibody production and immunological tolerance are
good systems for studying cellular differentiation despite
their overt complexity. The advantages of the systems lie
in the specific handle afforded by antigen and in the
temporal reference point of exposure to antigen or adjuvant.
Nossal has pointed out that immunological tolerance can be
discussed in terms of a decision between two alternative
pathways for an individual lymphocyte (1) (see Fig. 1). Such
concepts of stimulation of a differentiating cell, down one
or two or more alternative pathways, are commonplace in em-
bryology and epigenetics. Known inducers range from diffus-
able substances acting at long range to substances dependent
on cell-cell contacts (2).
Differences in the rate of entry into a state of
immunological unresponsiveness after the administration of
tolerogen (tolerance-inducing form of antigen) exist (3-6).
Sometimes these differences can be accounted for by differ-
ent methods of measuring responsiveness (precipitation,
antigen elimination, plaques), sometimes to different proto-
cols (intact animals, cell transfers, in vitro) and sometimes
to the antigen (immunogenic/non-immunoqenic, protein/carbo-
hydrate). However, in a series of classical experiments,
Chiller and his colleagues in cell transfer experiments have
shown that real differences exist in dose sensitivity and
rate of entry into a state of unresponsiveness, between tol-
erance induction in T and in B lymphocytes (4, 5, 7) and in
further experiments differences between spleen and bone
marrow B cells have been demonstrated (6).
Since all mechanisms demonstrated in disrupted systems
must eventually be related to physiological reality in intact
animals, it was decided that a study of factors affecting
the rate of induction in intact mice would be made. Experi-
ments have been started in an attempt to measure the induc-
tion of tolerance in different lines of B cells; some pre-
liminary results are included here. If observed differences
3