Table Of ContentSerono Symposia USA
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PROCEEDINGS IN THE SERONO SYMPOSIA USA SERIES
GENETIC MODELS OF IMMUNE AND INFLAMMATORY DISEASES
Edited by Abul K. Abbas and Richard A. Flavell
MOLECULAR AND CELLULAR ASPECTS OF PERIIMPLANTATION PROCESSES
Edited by S.K. Dey
THE SOMATOTROPHIC AXIS AND THE REPRODUCTIVE PROCESS IN HEALTH
AND DISEASE
Edited by Eli Y. Adashi and Michael O. Thorner
GHRH, GH, AND IGF-I: Basic and Clinical Advances
Edited by Marc R. Blackman, S. Mitchell Harman, Jesse Roth, and
Jay R. Shapiro
IMMUNOBIOLOGY OF REPRODUCTION
Edited by Joan S. Hunt
FUNCTION OF SOMATIC CELLS IN THE TESTIS
Edited by Andrzej Bartke
GLYCOPROTEIN HORMONES: Structure, Function, and Clinica/lmplications
Edited by Joyce W. Lustbader, David Puett, and Raymond W. Ruddon
GROWTH HORMONE II: Basic and Clinical Aspects
Edited by Barry B. Bercu and Richard F. Walker
TROPHOBLAST CELLS: Pathways for Maternal-Embryonic Commllnication
Edited by Michael J. Soares. Stuart Handwerger, and Frank Talamantes
IN VITRO FERTILIZA TION AND EMBRYO TRANSFER IN PRIMATES
Edited by Don P. Wolf. Richard L. Stouffer, and Robert M. Brenner
OVARIAN CELL INTERACTIONS: Genes to Physiology
Edited by Aaron J.W. Hsueh and David W. Schomberg
CELL BIOLOGY AND BIOTECHNOLOGY:
Novel Approaches to Increased Cellular Productivity
Edited by Melvin S. Oka and Randall G. Rupp
PREIMPLANTA TION EMBRYO DEVELOPMENT
Edited by Barry D. Bavister
MOLECULAR BASIS OF REPRODUCTIVE ENDOCRINOLOGY
Edited by Peter C.K. Leung. Aaron J.W. Hsueh. and Henry G. Friesen
MODES OF ACTION OF GnRH AND GnRH ANALOGS
Edited by William F. Crowley. Jr.. and P. Michael Conn
Continlled after Index
Serono Symposia USA
Norwell, Massachusetts
Abul K. Abbas Richard A. Flavell
Editors
Genetic Models of
Immune and
Inflammatory Diseases
With 23 Figures
i Springer
Abul K. Abbas, M.D. Richard A. Flavell. Ph.D.
Department of Pathology Section of Immunobiology
Brigham and W omen'S Hospital Yale University School of Medicine
Harvard Medical School New Haven, cr 06520
Boston. MA 02115 USA
USA
Proceedings of the International Symposium on Gene tic Models of Immune and Inftammatory Diseases
sponsored by Strano Symposia USA. Inc .. hdd October 20 to 23. 1994. in Savannah. Georgia .
For information on previous volumes. please contact Strono Symposia USA. Inc.
Ubn.ry of Congre505 Cataloging.in .Publieltion Dati
Gene tic models of immune and inflammatory diseases/edited by Aool K.
Abb.s and Richard A. R lvell.
p. Cm.
~ Proceedings of the International Symposium on Genetic Models of Im mune and Inflammatory Dis·
el ses, sponsored by Serono Symposia USA. Inc .. held October 20 to 23. 1994. in Savannah. Georgian_T. p.
\/erso.
Includes biblioJ!:raphical references and indue$.
ISBN.13,978-1-4612-7520-6 .·ISIIN·1J: 9711·1-4612·2376-4
001: 10.100719711-1..01612·2376-4
I. Autoimmunily-Animal mode ll-Congre·sKs. 2. Inflammation- Immunological aspects-Animal
model!-CongrC$5C5. 3. Tn.rugenie miee-CongrCSKS.. 4. Cytokines-Plthophysiology- Animal
models--Con&resses. I. Abbas. Abul K. II . Serono Symposia. USA. Ill . Inlernational Symposium on
GeTlC'tit Models of Immu~ and Inflammatory DisclOSC$ (1994: $annn.h. Ga.)
]DNLM: I. Immunily-genetic:s--<ongresses. 2. AUloimmunity-geTlC'ti<:s--«Jngresses. 1. Cytokines-
geTlC'lics--oongresses. 4. Immunologie Discascs-senetic:s-oongres5C$. 5. Models. Qc,netit--o:mgres5C$.
OW 540 G328 I996J
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I SJ)N· 13 : 978·1-4612.7S2~ Springer-Ve rlag Ne .. York Berlin Heidelberg SPIN 10524771
GENETIC MODELS OF IMMUNE AND
INFLAMMATORY DISEASES
Scientific Committee
Abul K. Abbas, M.D.
Harvard Medical School
Boston, Massachusetts
Richard A. Flavell, Ph.D.
Yale University School of Medicine
New Haven, Connecticut
Organizing Secretary
Leslie Nies
Serono Symposia USA, Inc.
100 Longwater Circle
Norwell, Massachusetts
Preface
This book contains the proceedings of the Serono Symposia USA interna-
tional symposium on Genetic Models of Immune and Inflammatory Dis-
eases held on October 20 to 23, 1994, in Savannah, Georgia. The advent of
methods for introducing genes into the germlines of mice, and for targeted
disruption of particular genes by homologous recombination, has provided
scientists in many disciplines with an extraordinarily powerful set of analyti-
cal tools. Some of the most informative applications of transgenic and gene
knockout technology have been in studies of lymphocyte development and
activation. The goal of this symposium was to bring together investigators
using these genetic approaches for analyzing the immune system, with a
view to defining common themes and novel directions.
Transgenic mice have a wide variety of important applications in immu-
nology. Defined proteins can be expressed in selected tissues throughout
development, thus acquiring the essential characteristic of "self" antigens.
Such models have been used to study how immune responses to these
artificially created "self" antigens are controlled. Antigen receptors of lym-
phocytes have been expressed as transgenes, and because lymphocytes are
endowed with the unique property of allelic exclusion, such transgenic mice
become essentially monospecific. Immunomodulatory agents have been
expressed in defined tissues or throughout the body, providing tools for
studying the functional consequences of dysregulated expression of biologi-
cal response modifiers.
The achievements that have come from analyses of gene knockout mice
are perhaps even more remarkable. The obligatory roles of many proteins
in lymphocyte development and function have been definitively established
in knockouts. Equally impressive are the surprises that have resulted from
many such studies, in which unexpected functions of particular proteins
have been revealed. At the same time, many knockout mouse models have
demonstrated the redundancy of cytokines and regulatory proteins, and the
efficiency of "backup" systems.
The next phase in the applications of transgenic and knockout mice is in
creating models for human diseases. This symposium strongly highlighted
the value of these approaches, and the enormous potential of methods of
vii
viii Preface
in vivo genetic manipulation for understanding pathologic disorders, such
as autoimmune and infectious diseases. There seems little doubt that this
potential will continue to be realized in the next few years.
We would like to acknowledge our gratitude to Serono Symposia USA,
Inc., for organizing the conference, and particularly to Leslie Nies and her
staff for their invaluable assistance with the meeting and the proceedings.
Luk van Parijs, a graduate student at Harvard, accepted the challenge of
summarizing the conference and editing the proceedings, and did both tasks
with care and thoughtfulness.
ABUL K. ABBAS
RICHARD A. FLAVELL
Contents
Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii
Contributors .............................................. Xlll
Part I. Autoimmunity
1. Intensification of Diabetes in B7-1 Transgenic Mice ....... 3
CHARLES A. JANEWAY, JR., FLORENCE SUSAN WONG,
SYLVIE GUERDER, EVA-PIA REICH, IRENE VISINTIN, AND
RICHARD A. FLAVELL
2. A Transgenic Window on Self-Reactive T Lymphocytes. . . . 16
JACQUES F.A.P. MILLER, WILLIAM R. HEATH, AND
JANETTE ALLISON
3. Induction and Breaking of Peripheral Tolerance .... . . . . . . 22
GUNTER J. HAMMERLING, JUDITH ALFERINK, IRIS FERBER,
ANDREAS LIMMER, AND BERND ARNOLD
4. T-Cell Development and Tolerance in Virus-Specific
Transgenic Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
PAMELA S. OHASHI
5. Inflammatory Disease in HLA-B27 Transgenic Rats. . . . . . . 44
JOEL D. TAUROG AND ROBERT E. HAMMER
Part II. Autoimmunity, Infections
6. The Role of CD40 Ligand in Regulation
of Immune Response ................................. 53
IQBAL S. GREWAL, JIANCHAO XU, AND RICHARD A. FLAVELL
IX
x Contents
7. Adventures in Antigen Presentation. . . . . . . . . . . . . . . . . . . . . 69
DAVID La
8. The Effect of MHC Encoding Transgenes on IDDM in
NOD Mice........................................... 82
RUBY QUARTEY PAPAFIO, DON HEALEY, LORRAINE O'REILLY,
PATRICIA HUTCHINGS, SUE DAY, AND ANNE COOKE
9. The Immunology of Leishmania Major Infection in Mice. . . 89
RICHARD M. LOCKs LEY
Part ill. Cytokines, Co-Stimulators, Tumor Immunity
10. The Regulatory Functions of Co-Stimulators Revealed
in Transgenic Mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
MICHAEL P. SETHNA, LUK VAN PARIJS, ARLENE H. SHARPE,
GORDON J. FREEMAN, AND ABUL K. ABBAS
11. B7-Deficient Mice Reveal an Alternative
Functional CTLA-4 Counterreceptor . . . . . . . . . . . . . . . . . . . . 107
FRANK BORRIELLO, ELIZABETH A. TIVOL, GORDON J. FREEMAN,
AND ARLENE H. SHARPE
12. Cytokine Transgenic Mice and Autoimmunity . . . . . . . . . . . . 121
MYUNGcSHlK LEE AND NORA SARVETNICK
13. Gaining Insights into the Ontogeny and Activation of T Cells
Through the Use of Gene-Targeted Mutant Mice ......... 129
TAK W. MAK
14. B7-Mediated Co-Stimulation of T Cells: CTLA-4 Can Deliver
Inhibitory Signals ..................................... 138
MATTHEW KRUMMEL AND JAMES P. ALLISON
Part IV. Cytokine Deletions
15. Lymphoid Organogenesis and Inflammation
Are Mediated by Lymphotoxin ..... '" .. . .. . . ... . .. .... 149
ALEXANDER KRATZ, DONNA M. BARTEN, ANTONIO CAMPos-NETO,
AND NANCY H. RUDDLE
Contents Xl
16. The Role of Interferon-a in the Development of
Type I Diabetes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
XIAOJIAN HUANG, BRUCE HULTGREN, SHARON PITTs-MEEK,
JIM HULLY, JIM MACLACHLAN, NOEL DYBDAL, AND
TIMOTHY A. STEWART
17. Cytokine-Deficient Mouse Mutants.. ...... . .... . . . . . . . .. 167
WERNER MOLLER
Author Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171
Subject Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 173
