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IMMUNOPHARMACOLOGY IN AUTOIMMUNE DISEASES AND TRANSPLANTATION
IMMUNOPHARMACOLOGY IN AUTOIMMUNE DISEASES AND TRANSPLANTATION
Edited by
Hans Erik Rugstad Rikshospitalet Oslo, Norway
Liv Endresen Rikshospitalet Oslo, Norway
and
(/>ystein F~rre Oslo Sanitetsforening Rheumatism Hospital Oslo, Norway
Springer Science+Business Media, LLC
Library of Congress Cataloglng-In-Publ1 cation Data
Immunopharmacology in autoimmune d i s e a s e s and t r a n s p l a n t a t i o n / e d i t e d by Hans Erik Rugstad and L1v Endresen and 0yste1n F0rre.
p. cm. Includes b i b l i o g r a p h i c a l r e f e r e n c e s and Index.
1. Autoimmune diseases—Immunotherapy. 2. T r a n s p l a n t a t i o n of organs, t i s s u e s , e t c . 3. Immunopharmacology. I. Rugstad, Hans Erik. I I . Endresen, L1v. I I I . F e r r e , 0yste1n. [DNLM: 1. Autoimmune Diseases—Immunology. 2. Autoimmune
D i s e a s e s — t h e r a p y . 3. Immunosuppressive Agents—pharmacology. 4. Immunosuppressive A g e n t s — t h e r a p e u t i c use. 5. Immunotherapy. 6. T r a n s p l a n t a t i o n Immunology. WD 305 1334] RC600.I48 1992 616.97'8061~dc20 DNLM/DLC for Library of Congress 92-49484
CIP
ISBN 978-1-4899-1169-8 ISBN 978-1-4899-1167-4 (eBook) DOI 10.1007/978-1-4899-1167-4
© Springer Science+Business Media New York 1992 Originally published by Plenum Press, New York in 1992 Softcover reprint of the hardcover 1st edition 1992
All rights reserved
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, recording, or otherwise, without written permission from the Publisher
CONTRIBUTORS
D. Adu Department of Nephrology, Queen Elizabeth Hospital, Birmingham B15 2T}, England
Dagfinn H. Albrechtsen Surgical Department, The National Hospital, University of Oslo, 0027 Oslo 1, Norway
0. Baadsgaard Department of Dermatology, University of Michigan Medical Center, 1910 A. Taubman Center, Ann Arbor, Michigan 48109
Jean-Fra~ois Bach Immunology Clinic, Necker Hospital, 75743 Paris Cedex 15, France
P. A. Bacon Department of Rheumatology, The University of Birmingham, The Medical School, Birmingham B15 2TT, England
Knut J. Berg Section for Nephrology, Department of Medicine, The National Hospital, University of Oslo, 0027 Oslo 1, Norway
David C. Blakey ICI Pharmaceuticals, Macclesfield SKIO 4TG, Cheshire, England
Marc D. Brown Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109
Lucienne Chatenoud Immunology Clinic, Necker Hospital, 75743 Paris Cedex 15, France
Kevin D. Cooper Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109
A. M. Denman Division of Immunological Medicine, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex HAl 3U}, England
D. J. Denman Division of Immunological Medicine, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex, HAl 3U}, England
J. Dupre University Hospital, The University of West em Ontario, London, Ontario N6A 5A5, Canada
Charles N. EUis Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109
Liv Endresen Institute of Clinical Biochemistry, The National Hospital, University of Oslo, 0027 Oslo 1, Norway
v
vi Contributors
GiUes FeutTen Clinical Research/Immunology, Sandoz Pharma Ltd., CH·4002 Basle, Switzerland
Marie L Foegh Department of Surgery, Georgetown University Medical Center, Washing. ton, D.C. 20007
0ystein F(lJTTe Oslo Sanitetsforening Rheumatism Hospital, N·OI72 Oslo 1, Norway
Mark S. Fradin Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109
LeifGjerstad Department of Neurology, The National Hospital, University of Oslo, 0027 Oslo 1, Norway
Sudhir Gupta Division of Basic and Clinical Immunology, University of California, Irvine, Irvine, California 92717
Graham Robert Vivian Hughes Lupus Arthritis Research Laboratory, The Rayne Institute, St. Thomas' Hospital, London SEI 7EH, England
Catherine Kalvenes Institute of Immunology and Rheumatology, The National Hospital, N·OI72 Oslo 1, Norway
Munther Andrawes Khamashta Lupus Arthritis Research Laboratory, The Rayne Institute, St. Thomas' Hospital, London SEI 7EH, England
Bruce W. Kirkham Rheumatology Unit, United Medical and Dental Schools, Guy's Hospital, London SEI 9RT, England
lens Kjeldsen.Kragh Institute of Immunology and Rheumatology, The National Hospital, N·0172 Oslo 1, Norway
Lars Klareskog Department of Clinical Immunology, Uppsala University Hospital, S· 751 85 Uppsala, Sweden
Robert L Kormos Department of Surgery, University Health Center of Pittsburgh, Univer· sity of Pittsburg, and the Veterans Administration Medical Center, Pittsburgh, Penn· sylvania 15213
Martin Lombard Institute of Liver Studies, King's College School of Medicine, London SE5 8RX, England
R. A. Luqmani Department of Rheumatology, The University of Birmingham, The Medical School, Birmingham B15 2TT, England
J. L. Mahon University Hospital, The University of Western Ontario, London, Ontario N6A 5A5, Canada
Leonard Makowka Department of Surgery, University Health Center of Pittsburgh, Uni· versity of Pittsburgh, and the Veterans Administration Medical Center, Pittsburgh, Pennsylvania 15213. Present address: Department of Surgery, Cedar Sinai Medical Center, Los Angeles, California 90048
Ove l. MeUbye Institute of Immunology and Rheumatology, The National Hospital, N·OI72 Oslo 1, Norway
Contributors vii
Luis Mieles Department of Surgery, University Health Center of Pittsburgh, University of Pittsburgh, and the Veterans Administration Medical Center, Pittsburgh, Pennsyl. vania 15213
Alfonso Monereo Department of Internal Medicine, La Paz Hospital, 28002 Madrid, Spain
Jacob B. Nawig Institute of Immunology and Rheumatology, The National Hospital, N·Ol72 Oslo 1, Norway
Robert B. Nussenblatt National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892
RolfNyberg.Hansen Department of Neurology, The National Hospital, University of Oslo, 0027 Oslo 1, Norway
Monika 0stensen Department of Rheumatology, University Hospital of Trondheim, 7006 Trondheim, Norway
R. G. Palmer Division oflmmunological Medicine, Clinical Research Centre, Northwick Park Hospital, Harrow, Middlesex HAl 3UJ, England. Present address: Solihull Hospi. tal, Solihull, West Midlands B91 2JL, England
Gabriel S. Panayi Rheumatology Unit, United Medical and Dental Schools, Guy's Hospi. tal, London SE1 9RT, England
Alison Quayle Institute of Immunology and Rheumatology, The National Hospital, N·Ol72 Oslo 1, Norway
Hans Erik Rugstad Department of Clinical Pharmacology, The National Hospital, Univer· sity of Oslo, N·oo27 Oslo 1, Norway
D. G. I. Scott Norfolk and Norwich Hospital, Norfolk, Norwich NR1 3SE, England
Dag SflITskaar Oslo Sanitetsforening Rheumatism Hospital, N·0172 Oslo 1, Norway
Thomas E. Starzl Department of Surgery, University Health Center of Pittsburgh, Univer· sity of Pittsburgh, and the Veterans Administration Medical Center, Pittsburgh, Pennsylvania 15213
C. R. StiUer University Hospital, The Unviersity of Western Ontario, London, Ontario N6A 5A5, Canada
Norman Tala! Clinical Immunology Section, Audie 1. Murphy Memorial Veterans Hospi. tal, and the Department of Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284
T. Talseth Section for Nephrology, Department of Medicine, The National Hospital, University of Oslo, 0027 Oslo 1, Norway
Morten H. Vam Medical Department A, The National Hospital, University of Oslo, N·0027 Oslo 1, Norway
Juan Jose Vazquez Department of Internal Medicine, La Paz Hospital, 28002 Madrid, Spain
Eric M. Veys Department of Rheumatology, Ghent University Hospital, University of Ghent, B·9000 Ghent, Belgium
viii Contributors
Beat von Graffenried Clinical Research/Immunology, Sandoz Pharma Ltd., CH-4002 Basle, Switzerland
John]. Voorhees Department of Dermatology, University of Michigan Medical Center, Ann Arbor, Michigan 48109
Kristian Waalen Department of Animal Genetics, National College of Veterinary Medicine, and the Institute of Immunology and Rheumatology, The National Hospital, 0033 Oslo 1, Norway. Present Address: Vaccine Department, National Institute of Public Health, N-0472 Oslo 4, Norway
Roger Williams Institute of Liver Studies, King's College School of Medicine, London SE5 8RX, England
Robert Winchester Department of Pediatrics, Division of Autoimmune and Molecular Diseases, Columbia University College of Physicians and Surgeons, New York, NY 10032
Yejun Zhao Department of Surgery, Georgetown University Medical Center, Washington, D.C. 20007
PREFACE
This book incorporates the latest advances in immunopharmacological treatment. One objective has been to provide appropriate bridges between the basic sciences of immunology and pharmacology on the one hand and clinical medicine on the other. A further intention has been to emphasize those advances in immunology and pharmacology that are of clinical importance while retaining those facts that, while not new, remain clinically useful.
The immunology section provides the necessary background for immunopharmacological treatment. The chapters on individual cell types include normal surface markers, mode of activation, and activation markers and functions in health and disease.
The chapters on pharmacology give comprehensive information on immunosuppressive drugs in regular use today, their biochemical and cellular mechanisms of action, pharmacokinetics, dosage regimens, therapeutic responses, adverse reactions, and drug interactions and tolerance. In addition, certain therapeutic principles that are still in an experimental phase are described, for example, immunotoxins, thymic hormones, and interleukins.
The book presents comprehensive information on various autoimmune diseases, the etiopathogenetic immune mechanisms where these are known, and the current possibilities for immunopharmacological intervention. The specific disease section also covers rare situations, fluctuations in disease patterns, and subgroups of patients and immunopharmacological treatment in these situations. Altogether, the book represents a practical textbook for clinicians and advanced students who want to be updated on therapeutic principles with regard to autoimmune diseases and transplantation.
The editors have made particular efforts to include references that were published recently. The group of outstanding authors from the United States, Canada, and Europe have each made a major commitment to present the very best literature in his or her field.
ix
CONTENTS
PART I. IMMUNOLOGY AND PATHOGENETIC MECHANISMS
Chapter 1 Human Immune Response Genes Robert Winchester
1. Clones and Repertoires ............................................ 3 2. Molecular Interactions in the Immune Response ....................... 4 3. Strategies for Receptor Diversity .................................... 6 4. MHC Polymorphism as an Adaptive Response......................... 6 5. Autoimmunity and T-Cell Regulation ................................ 6 6. Structure of MHC Molecules ....................................... 7 7. Functional Differences of Class I and Class II Molecules . . . . . . . . . . . . . . . . . 7 8. Genetic Organization of the MHC .................................. 8
8.1. DR Polymorph isms Define Haplotypes ........................... 9 8.2. Location of Allelic Differences ................................. 10
9. Immune Recognition Events in Class I MHC Diseases .................. 11 10. Immune Recognition Events in Class II MHC Diseases ................. 11 11. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Chapter 2 Accessory Cells Kristian Waalen and 0ystein FfchTe
1. Introduction ..................................................... 15 2. Processing of Antigens by Accessory Cells ............................ 15 3. The Importance of MHC Molecules for Accessory Cell Function. ......... 16 4. Accessory Cell Heterogeneity ....................................... 17
4.1. Monocytes and Macrophages ................................... 18 4.2. Dendritic Cells .............................................. 18
5. Markers and Characteristics of Accessory Cells (Dendritic Cells, Macrophages, and B Cells) ......................................... 20
xi
xii Contents
6. Functional Characteristics of Dendritic Cells in Chronic Inflammation .... . 6.1. T-Cell Activation Antigens Induced by Dendritic Cells in Vitro ..... . 6.2. Activation of T Cells and B Cells by Accessory Cells .............. .
7. Cytokine Production by Accessory Cells ............................. . 8. Accessory Cell Adhesion Molecules and Homing to Sites of Inflammation .. 9. Accessory Cells as Target for Immune Modulation ..................... .
9. 1. Immunomodulating Drugs .................................... . 9.2. Monoclonal Antibodies ...................................... . 9.3. Peptide Competition ......................................... . 9.4. Specific Inhibitors of Cytokines (Anticytokine Antibodies, Soluble
Receptors) ................................................. . 9.5. Cytokine-Toxin Chimeras .................................... . 9.6. Cytokines ................................................. . 9. 7. Vaccination ................................................ .
10. Conclusion ..................................................... . References
Chapter 3 B Cells in Autoimmunity 0ystein P0Tre, Kristian Waalen, Jens Kjeldsen-Kragh, Dag SrJrskaar, Ove J. Mellbye, and Jacob B. Natvig
20 20 21 22 23 24 24 25 25
26 26 26 26 27 27
1. Introduction ..................................................... 31 2. Organization and Expression of Immunoglobulin Genes ................. 32 3. Activation of B Cells ............................................. 34 4. Maturation of B Lymphocytes as Reflected by Expression of Cell Surface
Markers ......................................................... 34 5. B Cells, Autoantibodies, and Immune Complexes ...................... 36
5.1. Rheumatoid Factor ........................................... 37 5.2. Antinuclear Antibodies ....................................... 39 5.3. Antimitochondrial Antibodies .................................. 39 5.4. Other Antibodies and Circulating Immune Complexes. . . . . . . . . . . . .. 40
6. Drug-Induced Autoimmunity ....................................... 40 7. Immune Intervention ............................................. 41
7.1. Glucocorticoids .............................................. 41 7.2. Cytotoxic Drugs ............................................. 41 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
Chapter 4 T Lymphocytes in Autoimmunity and Transplantation Jens Kjeldsen-Kragh, Alison Quayle, Catherine Kalvenes, and 0ystein PrJrre
1. Introduction ..................................................... 45 2. The T-Cell Repertoire ............................................. 45 3. Antigen Recognition .............................................. 47 4. T-Cell Activation ................................................ 47
4.1. The TCR-CD3 Complex ...................................... 47
()ontents xili
4.2. Accessory Cell Markers ....................................... 47 4.3. T-Cell Activation Markers ..................................... 49
5. T Cells in Transplantation ......................................... 50 6. T Cells in Autoimmunity .......................................... 50
6.1. Breakdown of T-Cell Tolerance to Self-Antigens ................... 50 6.2. The Role of MHC Genes in Autoimmunity ...................... 51 6.3. Antigens Involved ............................................ 52 6.4. Restriction of TCR Gene Usage ................................ 52
7. Immune Intervention ............................................. 53 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
Chapter 5 Natural Killer Cells in Autoimmune Diseases: Function and Markers Dag Sm-skaar and 0ystein Fm-re
1. Introduction ..................................................... 59 2. Phenotype of NK Cells ............................................ 60 3. Lysis by NK Cells ................................................ 61 4. NK Cell Activity in Autoimmune Diseases ........................... 61
4.1. Rheumatoid Arthritis and Juvenile Rheumatoid Arthritis ........... 62 4.2. Systemic Lupus Erythematosus ................................. 62 4.3. Sjogren's Syndrome ........................................... 63
5. Effect of Antirheumatic Drugs on NK Cell Function. .. .. .. .. .. .... .... . 64 6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66
Chapter 6 Interleukins: Molecular and Biological Properties Sudhir Gupta
1. Introduction ....................... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 2. Interleukin-l ............................... ..................... 71
2.1. Molecular Characteristics of IL-l ............................... 72 2.2. Synthesis and Secretion of IL-l ................................. 72 2.3. IL-l Receptors ............................................... 74 2.4. Biological Activities of IL-l .................................... 74 2.5. IL-l Inhibitors ............................................... 77
3. Interleukin-2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77 3.1. Production of IL-2 ........................................... 78 3.2. Molecular Characteristics of IL-2 ............................... 78 3.3. IL-2 Receptor ............................................... 79 3.4. Regulation of IL-2R Expression ................................. 80 3.5. Biological Effects of IL-2 ...................................... 81
4. Interleukin-6 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 4.1. Molecular Structure of IL-6 .................................... 83 4.2. Regulation of IL-6 Expression .................................. 84
xiv Contents
4.3. IL-6 Receptor ............................................... 84 4.4. Biological Effects of IL-6 ...................................... 84
5. Interleukins in Rheumatoid Arthritis ................................ 85 6. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
Chapter 7 The Immunologic Network: Possibilities for aNew Immunopharmacology Norman Talal
1. Introduction ..................................................... 93 2. Monoclonal Anti-Ia Antibodies ..................................... 94 3. Therapy Targeted to T Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4. Therapy Directed at B Cells ........................................ 97 5. General Biological Approaches ..................................... 97
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98
PART II. PHARMACOLOGY AND GENERAL THERAPEUTIC PRINCIPLES OF IMMUNOMODULATING DRUGS
Chapter 8 Steroids Bruce W. Kirkham and Gabriel S. Panayi
1. Introduction .................................................... . 2. Pharmacokinetics ................................................ .
2. 1. Absorption ................................................. . 2.2. Distribution ................................................ . 2.3. Elimination ................................................ . 2.4. Drug Interactions ........................................... .
3. Side Effects .................................................... . 4. Subcellular Mechanisms of Action .................................. .
4. 1. Regulation of Gene Transcription .............................. . 4.2. Glucocorticoid Anti-inflammatory Actions ...................... .
5. Cellular Mechanisms of Action .................................... . 5.1. Cell Traffic ................................................ . 5.2. T-Lymphocyte Function ...................................... . 5.3. B-Lymphocyte Function ...................................... . 5.4. Lymphocyte Lysis ........................................... . 5.5. Natural Killer Cells and Antibody-Dependent Cellular Cytotoxicity .. . 5.6. Accessory Cell Function ...................................... . 5.7. Acute-Phase Response ....................................... . 5.8. Glucocorticoid Resistance .................................... .
6. Summary References
103 104 104 106 106 106 106 108 108 110 111 111 112 114 114 115 115 117 117 118 118
Contents
Chapter 9 Mode of Action of Thiopurines: Azathioprine and 6.Mercaptopurine Jean-Fra~ois Bach
xv
1. Introduction ..................................................... 123 2. Biochemical Effects of Azathioprine ................................. 123 3. Target Cells ..................................................... 124 4. Mode of Action .................................................. 125 5. Clinical Uses .................................................... 125 6. Immunological Follow-up .......................................... 126
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Chapter 10 Pharmacology and General Therapeutic Principles of Methotrexate Liv Endresen
1. Introduction .................................................... . 2. Biochemical Pharmacology ........................................ .
2.1. Transport across Cellular Membranes ........................... . 2.2. Enzyme Inhibition ........................................... . 2.3. Metabolism to Polyglutamate Forms ............................ . 2.4. 7 -Hydroxy-Methotrexate ..................................... . 2.5. Effects on Folate Stores ...................................... .
3. Pharmacokinetics ................................................ . 4. Theories for a Selective Action on Neoplastic Cells ................... . 5. Mechanisms of Cellular Resistance. High-Dose Therapy ................ . 6. Effects on the Immune System ..................................... . 7. Side Effects and Toxicity .......................................... . 8. Conclusion ..................................................... .
References
Chapter 11 Alkylating Agents A. M. Denman, D. ]. Denman, and R. G. Palmer
127 128 129 129 129 130 131 132 133 133 134 136 136 136
1. Introduction ..................................................... 139 2. Pharmacology of Alkylating Agents. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 3. Pharmacokinetics ................................................. 140 4. Immunosuppressive Effects ......................................... 142
4.1. General .................................................... 142 4.2. Suppressor Mechanisms ....................................... 143 4.3. Tolerance ................................................... 143 4.4. Nonspecific Immunity ........................................ 144 4.5. Immunoenhancement ......................................... 144
5. Immunosuppressive Effects in Clinical Use. . . . . . . . . . . . . . . . . . . . . . . . . . . . 144 6. Clinical Indications ............................................... 144
6.1. Rheumatoid Arthritis ......................................... 145 6.2. Vasculitis ................................................... 145
xvi Contents
6.3. Wegener's Granulomatosis .................................... . 6.4. Behc;et's Syndrome .......................................... . 6.5. Systemic Lupus Erythematosus ................................ . 6.6. Renal Disease .............................................. . 6.7. Pemphigus ................................................. . 6.8. Other Immune Disorders ..................................... . 6.9. Multiple Sclerosis ........................................... .
7. Mechanisms of Action ........................................... . 8. Dose Schedule .................................................. . 9. Side Effects .................................................... .
9.1. Hematology ................................................ . 9.2. Infections .................................................. . 9.3. Sterility ................................................... . 9.4. Neoplasia .................................................. . 9.5. Teratogenesis ............................................... . 9.6. Other Side Effects ................................ '.' ......... .
10. Analogues of Alkylating Agents ................................... . 11. Future Prospects ................................................. . 12. Conclusions .................................................... .
References
Chapter 12 Cyclosporin A: Pharmacology and Therapeutic Use in Autoimmune Diseases Gilles Feutren and Beat von Graffenried
1. Introduction .................................................... . 2. Pharmacological Basis ............................................ .
2.1. Biochemistry and Pharmacology ............................... . 2.2. Pharmacological Monitoring .................................. . 2.3. Mechanism of Action ........................................ .
3. Animal Models of Autoimmune Diseases ............................ . 3.1. Preventive Treatment ........................................ . 3.2. Curative Treatment .......................................... .
4. Clinic~l Trials in Autoimmune Diseases ............................. . 4.1. Rheumatoid Arthritis ........................................ . 4.2. Autoimmune Uveitis ........................................ . 4.3. Idiopathic Nephrotic Syndrome ................................ . 4.4. Psoriasis ................................................... . 4.5. Other Autoimmune Diseases .................................. .
5. Adverse Events ........... , ..................................... . 5.1. Infections .................................................. . 5.2. Lymphoproliferative Disorders ................................. . 5.3. Renal Dysfunction .......................................... . 5.4. Cyclosporin Nephropathy ..................................... . 5.5. Other Adverse Events ........................................ .
6. Conclusions References
145 146 146 146 146 147 147 147 147 148 149 149 149 150 151 152 152 152 153 154
159 159 159 160 161 162 162 163 163 163 164 164 165 166 168 168 168 168 169 169 170 171
Contents
Chapter 13 Nonsteroidal and Other Anti-inflammatory Drugs Yejun Zhao and Marie L. Foegh
xvii
1. Introduction ..................................................... 175 2. Arachidonic Acid Metabolites ...................................... 176 3. Cellular Sources of Eicosanoids ..................................... 177 4. Cell-Cell Interaction ............................................. 178 5. In Vitro and in Vivo Effects of Eicosanoids and Platelet-Activating Factor on
the Cell-Mediated Immune Response ................................ 178 5.1. General ., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 178 5.2. Prostaglandins ............................................... 178 5.3. Thromboxane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179 5.4. Leukotrienes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 180 5.5. Lipoxins and Hydroxyeicosatetraenoic Acids ...................... 181 5.6. Platelet-Activating Factor ...................................... 182 5.7. Monitoring of Immunoreactive TXBz in Organ Rejection-A Cell-
Mediated Immune Response ................................... 182 6. Treatment with Prostaglandins and Inhibitors of Thromboxane and
Leukotriene Synthesis ............................................. 182 6.1. Experimental ................................................ 182 6.2. Clinical .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 183
7. Transplant Atherosclerosis-Chronic Rejection ........................ 184 8. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 184
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 185
Chapter 14 Anti-T-Cell Monoclonal Antibodies as Immunosuppressive Agents Lucienne Chatenoud and Jean-Fran~ois Bach
1. Introduction .................................................... . 1. 1. Basic Characteristics of Monoclonal Antibodies Compared to
Polyclonal Antisera .......................................... . 1.2. The Array of T-Cell Antigens ................................. . 1.3. Mode of Action of Therapeutic Monoclonal Antibodies .......... " .
2. Experimental Data ............................................... . 2.1. Murine Models ............................................. . 2.2. Monkey Models ............................................. .
3. Clinical Activity of Anti-T-Cell Monoclonal Antibodies ............... . 3.1. OKT3 ..................................................... . 3.2. Other Anti-Pan T-Cell Monoclonal Antibodies ................... . 3.3. Anti-IL-2 Receptor Monoclonal Antibody ....................... .
4. Antimonoclonal Sensitization ...................................... . 5. Conclusions .................................................... .
References
189
190 191 192 193 193 195 196 196 197 198 198 200 200
xviii Contents
Chapter 15 Immunotoxins David C. Blakey
1. Introduction 2. 3. 4. 5.
Preparation and Cytotoxic Properties of Immunotoxins in Vitro .......... . Properties of A-Chain and RIP Immunotoxins in Vivo .................. . Clinical Trials of Immunotoxins in Cancer ........................... . Immunotoxins in Transplantation ................................... . 5.1. Bone Marrow Transplantation ................................. . 5.2. Organ Transplantation ....................................... .
6. Immunotoxins in Autoimmune Disease .............................. . 7. Conclusions .................................................... .
References
Chapter 16 Interferons, Thymic Hormones, and Interleukins Eric M. Veys
205 206 208 210 211 211 212 213 214 214
1. Introduction ..................................................... 21 7 2. Thymic Hormones ................................................ 218
2.1. Thymic Hormones in Autoimmune Diseases ...................... 219 2.2. Thymic Hormones in the Treatment of RA ....................... 220
3. Interferons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 3. 1. Interferons in Autoimmune Diseases ............................ 221 3.2. IFN-'Y in the Rheumatoid Joint Environment ..................... 222 3.3. IFN-'Y in the Treatment of RA ................................. 222
4. Summary and Prospects ........................................... 223 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 224
Chapter 17 Strategy in Immunosuppression Jean-Fran{ois Bach
1. Introduction .................................................... . 2. Immunologic Mechanisms ......................................... . 3. Duration of Disease .............................................. . 4. Severity of the Disease: The Risk-Benefit Ratio ...................... . 5. Risks of Intense or Chronic Immunosuppression ...................... . 6. Drug Combination ............................................... . 7. Conclusions .................................................... .
References
227 228 228 229 229 229 230 231
Contents
Chapter 18 Immunosuppressive Drugs: The Need for Therapeutic Drug Monitoring Hans Erik Rugstad
1. Value and Limitations of Therapeutic Drug Monitoring of Immunosuppressive Drugs ......................................................... .
2. Cyclosporine A ................................................. . 2.1. Program for Monitoring CyA .................................. . 2.2. Assay Methods, Significance of Metabolites, and Biological Specimen 2.3. Pharmcokinetic Considerations ................................ . 2.4. Therapeutic Range .......................................... .
3. Azathioprine and 6.Mercaptopurine ................................ . 4. Methotrexate ................................................... . 5. Alkylating Agents ............................................... . 6. Glucocorticoids ................................................. . 7. Pharmcokinetic Interactions of Immunosuppressive Drugs ............... . 8. Conclusion ..................................................... .
References
Chapter 19 Immunopharmacological Treatment during Pregnancy and Lactation Monika 0stensen
xix
233 234 235 235 237 237 239 240 241 242 242 243 243
1. Introduction ..................................................... 245 1.1. Drug Disposition in the Gravida ................................ 246 1. 2. Placental Transfer of Drugs .................................... 246 1.3. Drug Disposition in the Fetus .................................. 246 1.4. Drug Excretion in Breast Milk ................................. 247
2. Corticosteroids ................................................... 247 2.1. Animal Studies .............................. :............... 247 2.2. Human Studies .............................................. 247 2.3. Corticosteroids in Autoimmune Diseases ......................... 248 2.4. Lactation ................................................... 248 2.5. Conclusion .................................................. 249
3. Azathioprine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 249 3.1. Animal Studies .............................................. 249 3.2. Azathioprine in Human Pregnancy .......................... " .. 249 3.3. Lactation ................................................... 250 3.4. Conclusion .................................................. 250
4. Cyclosporine A .................................................. 250 4.1. Animal Studies .............................................. 251 4.2. Human Studies .............................................. 251 4.3. Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 4.4. Conclusion .................................................. 252
5. Cytostatic Drugs ................................................. 252 5.1. Cyclophosphamide . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 252 5.2. Chlorambucil ................................................ 252 5.3. Methotrexate ................................................ 253
xx Contents
5.4. Conclusion .................................................. 253 6. Antirheumatic Disease-Modifying Drugs .............................. 254
6.1. Sulfasalazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 254 6.2. Gold Compounds ............................................ 254 6.3. Antimalarial Drugs ........................................... 255 6.4. Penicillamine ................................................ 256 6.5. Conclusion .................................................. 256
7. Drugs during Pregnancy and Lactation: General Recommendations ........ 257 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 257
PART III. IMMUNOTHERAPY IN AUTOIMMUNE DISEASE
Chapter 20 Systemic Lupus Erythematosus and Related Syndromes Alfonso Monereo, Munther Andrawes Khamashta, Juan Jose Vazquez, and Graham Robert Vivian Hughes
1. Introduction ..................................................... 263 2. Nonsteroidal Anti-inflammatory Drugs ............................... 264 3. Antimalarials .................................................... 265 4. Corticosteroids ................................................... 266 5. Steroid Pulse Therapy ............................................. 266 6. Immunosuppressives ........ ,...................................... 267 7. Other Therapeutic Measures ....................................... 268
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269
Chapter 21 Immunopharmacology of Vasculitic Syndromes P. A. Bacon, R. A. Luqmani, D. G. 1. Scott, and D. Adu
1. Introduction ..................................................... 273 2. Cyclophosphamide ................................................ 274
2.1. Use of Cyclophosphamide in Necrotizing Vasculitides .............. 274 2.2. Cyclophosphamide Regimens ................................... 279
3. Therapy of Nonnecrotizing Systemic Vasculitides. . . . . . . . . . . . . . . . . . . . . . . 284 3.1. Giant Cell Arteritis/Polymyalgia Rheumatica . . . . . . . . . . . . . . . . . . . . . . 284 3.2. Takayasu's Arteritis ........................................... 285
4. Other Immunosuppressive Therapies in Vasculitis ...................... 285 4.1. Azathioprine .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285 4.2. Cyclosporine A .............................................. 286 4.3. Therapeutic Apheresis ........................................ 286
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 287
Contents
Chapter 22 Immunotherapy in Autoimmune Liver Disease Martin Lombard and Roger Williams
xxi
1. Introduction ..................................................... 291 2. Autoimmune Disease Involving Biliary Epithelium ..................... 291
2.1. Primary Biliary Cirrhosis ...................................... 291 2.2. Primary Sclerosing Cholangitis ................................. 295
3. Autoimmunity Involving Liver Parenchymal Cells ...................... 297 3.1. Autoimmune Chronic Active Hepatitis .......................... 297 3.2. Immunotherapy in AICAH .................................... 298 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299
Chapter 23 Insulin-Dependent Diabetes Mellitus ]. L. Mahon, J. Dupre, and C. R. Stiller
1. Introduction .................................................... . 2. Pathogenetic Considerations Relevant to Immunomodulation for Human
100M ......................................................... . 3. Selected Immunotherapeutic Trials in 100M of Recent Onset ........... . 4. Conclusion ..................................................... .
References
Chapter 24 Immunoregulatory Treatment in Inflammatory Bowel Disease Morten H. Vatn
301
301 304 309 310
1. Introduction ..................................................... 313 2. Acute Severe Ulcerative Colitis and Crohn's Disease ................... 314 3. Corticosteroids in Chronic Active Ulcerative Colitis. . . . . . . . . . . . . . . . . . .. 315 4. Corticosteroids in Distal Active Ulcerative Colitis, Proctitis, and
Proctosigmoiditis ...... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 316 5. Corticosteroids in Quiescent Colitis ................................. 316 6. Azathioprine in Ulcerative Colitis ................................... 317 7. Cromoglycate in Ulcerative Proctocolitis ............................. 317 8. Corticosteroid Therapy of Acute and Active Crohn's Disease .......... ,. . . 317 9. Maintenance Treatment in Crohn's Disease ........................... 318
10. The Treatment of Relapse or Chronic Crohn's Disease .................. 318 11. Azathioprine Therapy in Active Crohn's Disease....................... 319 12. Azathioprine Therapy during Remission in Crohn's Disease .............. 319 13. Azathioprine and 6-Mercaptopurine as Prednisone-Sparing Treatment in
Crohn's Disease .................................................. 319 14. Summary of the Experience with Azathioprine in Crohn's Disease ........ 320 15. Dosage and Follow-up of Patients on Azathioprine ...................... 320 16. Side Effects of Azathioprine ........................................ 320 17. Cyclosporine A in the Treatment of Inflammatory Bowel Oisease ......... 321
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18. Other Immunoregulatory Agents .................................... 321 19. Immunoregulatory Treatment of IBD in Children. . . . . . . . . . . . . . . . . . .. . . . 321 20. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
Chapter 25 Disorders of Neuromuscular Transmission Rolf Nyberg-Hansen and Leif Gjerstad
1. Introduction ..................................................... 325 2. Myasthenia Gravis ................................................ 326
2.1. Pathogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326 2.2. Thymectomy ................................................ 327 2.3. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329 2.4. Azathioprine and Cyclophosphamide ............................ 329 2.5. Plasma Exchange ............................................ 330 2.6. Cyclosporine A .............................................. 330
3. The Lambert-Eaton Myasthenic Syndrome ........................... 331 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332
Chapter 26 Immune Therapy for Autoimmune Uveitis Robert B. Nussenblatt
1. Introduction ..................................................... 335 2. Anterior Uveitis ................................................. 336
2.1. Therapeutic Approaches ...................................... 336 2.2. Secondary Effects of Local Corticosteroid Therapy ................. 337 2.3. Other Approaches to Therapy. . . . .. . . .. . . .. . . . . . . . . . . . . . . . . . .. . 337
3. Diseases Involving the Intermediate and Posterior Segment of the Globe ... 338 4. Evaluation of the Posterior Uveitis Patient ............................ 339 5. Therapeutic Approaches to the Treatment of Severe Bilateral Endogenous
Uveitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 339 5.1. Use of Cytotoxic Agents ...................................... 340 5.2. The Use of Cyclosporine in the Treatment of Severe Endogenous
Uveitis ..................................................... 340 6. Other Approaches to Therapy ...................................... 341
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342
Chapter 27 Cyclosporine A in the Treatment of Dermatologic Diseases Mark S. Fradin, Marc D. Brown, Charles N. Ellis, Kevin D. Cooper, and John]. Voorhees
1. Introduction ..................................................... 345 2. Pharmacology of Cyclosporine ...................................... 346 3. Clinical Applications ............................................. 346
3. 1. Psoriasis .................................................... 346
Contents
3.2. Bullous Diseases ............................................ . 3.3. Beh<;et's Disease ............................................ . 3.4. Dermatomyositis/Polymyositis .................................. . 3.5. Atopic Dermatitis ........................................... . 3.6. Alopecia .................................................. . 3.7. Pyoderma Gangrenosum ...................................... . 3.8. Systemic Lupus Erythematosus ................................ . 3.9. Progressive Systemic Sclerosis ................................. .
4. Conclusion ..................................................... . References
Chapter 28 Immunotherapy in Kidney Diseases Knut]. Berg and Tore T alseth
xxiii
349 350 351 351 352 352 353 354 354 354
1. Introduction ..................................................... 357 2. Immunosuppressive Treatment of Glomerulonephritides ................. 358
2.1. Rapidly Progressive Glomerulonephritis .......................... 358 2.2. Glomerulonephritis with Nephrotic Syndrome.............. .. .. .. . 359
3. Effect of CyA in Posttransplant Glomerulonephritis in Renal Allografted Patients ......................................................... 364 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 365
Chapter 29 Mechanisms Involved in Immunomodulatory Treatment of Rheumatoid Arthritis Lars Klareskog
1. Introduction ..................................................... 369 2. Aspects on the Immunopathogenesis of Inflammatory JOint Disease,
Particularly RA .................................................. 369 3. Possible Immunomodulatory Effects of Currently Routinely Used Drugs in RA 370
3.1. Antimalarials ................................................ 370 3.2. Gold Compounds ............................................ 371 3.3. D-Penicillamine .............................................. 371 3.4. Sulfasalazine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372
4. Corticosteroids and Nonsteroidal Anti-inflammatory Drugs .............. 372 4.1. Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 372 4.2. Nonsteroidal Anti-inflammatory Drugs ........................... 372
5. Cytotoxic Drugs .................................................. 373 5.1. Cyclophosphamide ........................................... 373 5.2. Methotrexate ................................................ 373 5.3. Concluding Comment on Conventional Treatment ................. 373
6. Experimental Immunomodulatory Treatments .......................... 374 6.1. Cyclosporine A .............................................. 374 6.2. Monoclonal Antibody Treatment ............................... 375
7. Concluding Remark ............................................... 375 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 376
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PART IV. IMMUNOTHERAPY IN ORGAN AND BONE MARROW TRANSPLANTATION
Chapter 30 Immunotherapy in Organ Transplantation Luis Mieles, Robert L. Konnos, Leonard Makowka, and Thomas E. Starzl
1. Introduction ..................................................... 381 2. Immunosuppression in Liver Transplantation .......................... 382
2.1. Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 382 2.2. Cyclosporine Concentration Monitoring....................... .. . 384 2.3. Steroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 384 2.4. Azathioprine ................................................ 385
3. Immunosuppression in Renal Transplantation .......................... 385 3.1. Cyclosporine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 3.2. Azathioprine ................................................ 386 3.3. Prednisone .................................................. 386
4. Immunosuppression in Multiorgan Transplantation........... ........... 387 5. Treatment of Acute Rejection ...................................... 387
5.1. Steroids .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 5.2. OKT3 ...................................................... 387 5.3. ALG . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388
6. Immunosuppression in Cardiac Transplantation ........................ 388 6.1. Cyclosporine .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 6.2. Azathioprine ................................................ 388 6.3. Steroids .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 389 6.4. Rabbit Antithymocyte Globulin and OKT3 ....................... 389 6.5. Monitoring for Rejection ...................................... 389
7. Immunosuppression in Pulmonary and Cardiopulmonary Transplantation '" 390 8. Complications of Immunosuppression ................................ 390
8.1. Opportunistic Infections ....................................... 390 8.2. De Novo Cancers ............................................ 391
9. Donor Pretreatment ............................................... 391 10. New Developments in Immunosuppression ............................ 391 11. FK-506 ......................................................... 392
11.1. Advantages of FK-506 over Other Immunosuppressive Regimens .. . . . 392 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 394
Chapter 31 Bone Marrow Transplantation Dagfinn H. Albrechtsen
1. Introduction ..................................................... 397 2. Cytoreductive Therapy to Eradicate Disease ........... ~ . . . . . . . . . . . . . . . 398
2.1. Malignant Disease ............................................ 398 2.2. Nonmalignant Disease ........................................ 399
3. Prevention of Graft Rejection ..... " " .. .. .. .. .... .................. 399 3.1. Immunobiology of Rejection ................................... 399
Contents
3.2. Prevention of Rejection ...................................... . 3.3. Prevention of Rejection in High-Risk Patients .................... .
4. Prevention of Graft versus Host Disease ............................. . 4.1. Immunobiology of GVHD .................................... . 4.2. Prevention of GVHD ........................................ .
5. Treatment of Graft versus Host Disease .............................. . 5.1. Acute GVHD .............................................. . 5.2. Chronic GVHD ............................................ . References
Index
xxv
400 400 401 401 402 405 405 405 406
409
