Table Of ContentImmunotherapy of Diabetes
and
Selected Autoimmune Diseases
Editor
GeorgeS. Eisenbarth, M.D., Ph.D.
Chief Immunology Section
Joslin Diabetes Center
Boston, Massachusetts
Boca Raton London New York
CRC Press, Inc.
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First published 1989 by CRC Press
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Library of Congress Cataloging-in-Publication Data
Immunotherapy of diabetes and selected autoimmune diseases / editor.
George S. Eisenbarth.
p. cm.
Includes bibliographies and index.
ISBN 0-8493-4558-8
1. Diabetes--Immunotherapy. 2. Autoimmune disease-
-Immunotherapy. I. Eisenbarth, George S.
[DNLM: 1. Autoimmune Diseases--immunology. 2. Diabetes Mellitus.
Insulin-Dependent--immunology. WK 810 1339]
RC661.155144 1989
616.4 ‘6206--dcl9
DNLM/DLC
for Library of Congress 88-37170
A Library of Congress record exists under LC control number: 88037170
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ISBN 13: 978-1-315-89434-8 (hbk)
ISBN 13: 978-1-351-07344-8 (ebk)
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INTRODUCTION
In the past decade the tools of genetics and immunology have begun to impact in a
dramatic manner on our understanding of a series of human immune disorders. A disease
such as Type I diabetes, in this time period has gone from being of acute "viral etiology"
to being a prototypic chronic predictable autoimmune disease, complete with two excellent
animal models. It is remarkable for our concepts concerning such a common (.3% of the
population) and ancient disease to change so radically. As Type I diabetes is added to the
list of morbid immune disorders classified as organ specific autoimmune diseases, our
inability to effectively treat these diseases becomes more apparent. It is likely, as the contents
of this book will illustrate, that effective therapy for any of these disorders will have wide
ramifications. It should be readily apparent that for each of the diseases discussed, including
Type I diabetes, Graves' ophthalmopathy, uveitis, Cogan's syndrome, multiple sclerosis,
and gonadal disorders, there are three or more additional autoimmune disorders awaiting
effective therapy. The disorders covered were chosen to reflect the range of current knowledge
in organ specific autoimmunity. I believe that our current state of knowledge is analogous
to the use of airpower at the beginning of World War I. Man had learned to fly, could better
discern the enemy with his biplanes, was frustrated with his attempts to bomb the enemy
with hand-held grenades, but knew that an effective weapon was at hand. One of the major
proofs of an immune-mediated disease is effectiveness of immunotherapy, and detailed in
the three chapters covering the animal models are the specific therapies which effectively
help to define the disease. Effective therapy for autoimmunity in man is at hand in a drug
such as cyclosporine, but as several chapters will review, imaginative therapies must be
developed to use the drug but avoid renal toxicity. For each of the diseases, and in consid-
erable detail for Type I diabetes as a prototypic autoimmune disease, our current knowledge
of disease pathogenesis is reviewed. Knowledge of pathogenesis is essential for deciding
when immunotherapy will be efficacious, and judging the efficacy of current and future
therapies. As a clinician caring for patients with Type I diabetes, and now as a clinician
dealing with pre-Type I diabetics, I can see that our progress in this area appears too slow.
I have observed too many children, predicted to become diabetic, actually become diabetic.
It is my hope that a volume such as the present one, which defines the commonness of
problems and needs for effective immunomodulator therapy, will speed the development of
widely applicable and safe therapy.
THE EDITOR
GeorgeS. Eisenbarth, M.D., Ph.D., is Chief of the Section of Immunology at the
Joslin Diabetes Center and Associate Professor in the Department of Medicine, Harvard
Medical School, Brigham and Women's Hospital, New England Deaconess Hospital, Boston,
Massachusetts.
Dr. Eisenbarth graduated from Columbia College, where he held a Pulitzer scholarship
in 1969. He obtained his Ph.D. degree in Physiology in 1974 and M.D. degree in 1975
from Duke University.
Dr. Eisenbarth is a member of the American Diabetes Association, the American Society
for Clinical Investigation, the American Federation for Clinical Research, and the Immu-
nological Sciences Study Section of the National Istitutes of Health.
Among other awards, Dr. Eisenbarth has received the Outstanding Scientific Achieve-
ment Award of the American Diabetes Association (Lilly Award) and the Weitzmann Mem-
orial Award of the American Endocrine Society.
Dr. Eisenbarth has presented over 40 invited lectures at national and international meet-
ings and guest lectures at universities and institutes. He has published more than 150 research
papers. His current major research interests include the pathogenesis of autoimmune en-
docrine disorders, including Type I diabetes, with a major emphasis on predicting the disorder
and immunopathogenesis.
CONTRIBUTORS
Nancy B. Allen, M.D. Peter C. Colman, M.B.B.S., M.D.
Assistant Professor Director, Endocrine Laboratory
Department of Medicine Department of Diabetes and Endocrinology
Division of Rheumatology and Royal Melbourne Hospital
Immunology Parkville, Victoria, Australia
Duke University Medical Center
Durham, North Carolina Jennifer J. Cook
Research Fellow
Roger Assan, M. D. Department of Endocrinology and Diabetes
Professor and Head Royal Children's Hospital
Department of Diabetes Parkville,Victoria, Australia
Bichat Hospital
Paris, France John M. Court, M.B.B.S.
Director
Jean-Francois Bach, M.D., Ph.D. Department of Adolescent Medicine
Professor and Head Royal Children's Hospital
Department of Immunology Parkville, Victoria, Australia
Necker Hospital
Paris, France C. Christine Cox, M.D.
Associate in Medicine
Jurgen Beyer Department of Medicine
Professor Doctor Division of Rheumatology and
Departments of Internal Medicine, Immunology
Endocrinology and Metabolism Duke University Medical Center
Johannes Gutenberg University Hospital Durham, North Carolina
Mainz
Mainz, West Germany Brian Dean, M.Sc.
Scientist-in-Charge
Christian Boitard, M.D. Endocrine Laboratory
Department of Immunology Royal Melbourne Hospital
Necker Hospital Parkville, Victoria, Australia
Paris, France
Roberto de Bara, M.D.
Pierre Bougneres, Ph.D. Senior Staff Fellow
Department of Pediatric Endocrinology National Eye Institute
Saint Vincent de Paul Hospital National Institutes of Health
Paris, France Bethesda, Maryland
Dina Burstein, B.S. John Dupre, F.R.C.P. (C),
Medical Student F.R.C.P. (London), F.A.C.P.
Division of Diabetes Professor
University of Massachusetts Medical Department of Medicine
Center University of Western Ontario
Worcester, Massachusetts London, Ontario, Canada
L. Michael Cobo, M.D. George S. Eisenbarth, Ph.D., M.D.
Associate Professor Chief
Department of Ophthalmology Immunology Section
Duke University Medical Center Joslin Diabetes Center
Durham, North Carolina Boston, Massachusetts
Nadir R. Farid, M.B.B.S., Masakazu Hattori, M.D., Ph.D.
M.R.C.P.(U.K.), Investigator
F.R.C.P.(C.) F.A.C.P. Research Division
Professor of Medicine Joslin Diabetes Center
and Chief of Endocrine Division Boston, Massachusetts
Department of Medicine
Memorial University of Newfoundland Barton F. Haynes, M.D.
St. John's Newfoundland, Canada Professor, Department of Medicine
Chief, Division of Rheumatology and
Gilles Feutren, M.D. Immunology
Clinical Immunology Unit Duke University Medical Center
Necker Hospital Durham, North Carolina
Paris, France
Irene Hudson, Ph.D.
Dale L. Greiner, Ph.D. Statistician
Assistant Professor Royal Children's Hospital}
Department of Pathology Parkville, Victoria, Australia
University of Connecticut Health Center
Farmington, Connecticut Hiroshi lkegami, M.D., Ph.D.
Research Fellow
David A. Haner, M.D.
Research Division
Associate Professor of Neurology
Joslin Diabetes Center
Neurology Division, Department of
Boston, Massachusetts
Medicine
Center for Neurologic Diseases
George J. Kahaly, M.D.
Brigham & Women's Hospital
Internist and Endocrinologist
Harvard Medical School
Department of Internal Medicine,
Boston, Massachusetts
Endocrinology and Metabolism
University Hospital
Toshiaki Hanafusa, M.D.
Mainz, West Germany
Assistant Professor
2nd Department of Internal Medicine
Richard J. KeUer, M.D.
Osaka University Medical School
Assistant in Endocrinology
Osaka, Japan
Department of Medicine
Children's Hospital
Eugene S. Handler, Ph.D.
Boston, Massachusetts
Professor of Medicine-Cell Biology
Division of Diabetes
University of Massachusetts Medical Vicki E. Kelley, Ph.D.
Center Associate Professor
Worcester, Massachusetts Department of Medicine
Harvard Medical School
Leonard C. Harrison, M.B.B.S., M.D., Boston, Massachusetts
D.Sc.
Professor and Director Ulrich Kiesel, Dipi.-Biol.
Burnet Clinical Research Unit Clinical Department
Walter and Eliza Hall Institute Diabetes Research Institute
Parkville, Victoria, Australia Dusseldorf, West Germany
Hubert Kolb, Ph.D. Allen D. Roses, M.D.
Associate Professor of Immunology Professor and Chief
University of Dusseldorf Division of Neurology
Dusseldorf, West Germany Department of Medicine
Duke University Medical Center
Noel Maclaren, M.D. Durham, North Carolina
Professor and Chairman
Department of Pathology and Laboratory Aldo A. Rossini, M.D.
Medicine Professor of Medicine
University of Aorida College of Medicine Division of Diabetes
Gainesville, Aorida University of Massachusetts Medical
Center
F. Ian R. Martin, M.D. Worcester, Massachusetts
Physician in Charge
Department of Diabetes/Endocrinology T. Sato, M.D., Ph.D.
Royal Melbourne Hospital Research Fellow
Parkville, Victoria, Australia Research Division
Joslin Diabetes Center
Rex M. McCallum, M.D. Boston, Massachusetts
Assistant Professor
Department of Medicine Michael Schmidt
Division of Rheumatology and Student of Medicine
Immunology Clinical Department
Duke University Medical Center Diabetes Research Institute
Dusseldorf, West Germany
John P. Mordes, M.D.
Associate Professor of Medicine Janet Silverstein, M.D.
Division of Diabetes Associate Professor
University of Massachusetts Medical Department of Pediatrics
Center University of Aorida
Worcester, Massachusetts Gainesville, Aorida
Robert B. Nussenblatt, M.D. Calvin R. Stiller, M.D., F.R.C.P.
Clinical Director Professor, Department of Medicine
National Eye Institute University of Western Ontario
National Institutes of Health Chief, Multi Organ Transplant Service
Bethesda, Maryland University Hospital
London, Ontario, Canada
Alan G. Palestine, M.D.
Chief Terry Strom, M.D.
Clinical Immunology Section Professor
National Eye Institute Department of Medicine
National Institutes of Health Harvard Medical School
Bethesda, Maryland Boston, Massachusetts
Steven L. Rabinowe, M.D. Seiichiro Tarui, M.D., Ph.D.
Assistant Professor Professor and Chairman
Department of Medicine 2nd Department of Internal Medicine
Harvard Medical School Osaka University Medical School
Boston, Massachusetts Osaka, Japan
Garry L. Warne, M.B.B.S. George A. Werther, M.B.B.S., M.D.
Director Deputy-Director
Department of Endocrinology and Diabetes Department of Endocrinology and Diabetes
Royal Children's Hospital Royal Children's Hospital
Parkville, Victoria, Australia Parkville, Victoria, Australia
Howard L. Weiner, M.D. N. Yano, M.D.
Robert L. Kroc Associate Professor Research Fellow
of Neurologic Diseases Research Division
Neurology Division, Department of Joslin Diabetes Center
Medicine Boston, Massachusetts
Center for Neurologic Diseases
Brigham & Women's Hospital
Department of Medicine
Harvard Medical School
Boston, Massachusetts
This book is dedicated to the individuals who have graciously participated
in research trials of immunotherapy and shared, in a very personal way, the
uncertainty of clinical research.
