Mechanisms of Immune Regulation

Transcription

1 Mechanisms of Immune Regulation

2 Chemical Immunology Voi. 58 Series Editors Luciano Adorini, Milan Arai Ken-ichi, Tokyo Frank W. Fitch, Chicago, Ill. Kimishige Ishizaka, La Jolla, Calif. Peter J. Lachmann, Cambridge Byron H. Waksman, New York, N.Y. KARG E R Basel Freiburg Paris London New York New Delhi Bangkok Singapore Tokyo Sydney

3 Mechanisms of Immune Regulation Volume Editor Richard D. Granstein, Charlestown, Mass. 12 figures and 8 tables, 1994 KARG E R Basel Freiburg Paris London New York New Delhi Bangkok Singapore Tokyo Sydney

4 Chemical Immunology Formerly published as Progress in Allergy' Founded 1939 by Paul Kallòs Bibliographic Indices This publication is listed in bibliographic services, including Current Contents and Index Medicus. Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection απd dosage set forth in this text are in accord with current recommendations απd practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy απd drug reactions, the reader is urged to check the package insert for each drug for any change in indications απd dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new απd/or infrequently employed drug. AlI rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Copyright 1994 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland) Printed in Switzerland on acid-free paper by Thür AG Offsetdruck, Pratteln ISBN

5 Contents Preface XIII Mechanisms of Regulation T Cell Tolerance Vacchío, M.S.; Ashwell, J.D. (Bethesda, Md.) 1 Intτoduction 1 Tolerance Defined 2 How Is Tolerance Established? 3 Clonal Deletion 3 Deletion in the Thymus 3 Variability in TCR/Ligand Interactions that Affect Clonal Deletion 7 Types of Thymic APC Responsible for Clonal Deletion 9 Cellular Mechanisms of Clonal Deletion 11 Peripheral T Cell Deletion 11 Anergy 13 Thymocyte Anergy 13 Induction of Anergy in Peripheral T Cells 14 Mechanism of Anergy 17 Why Peripheral Anergy? 20 Other Mechanisms of Unresponsiveness 20 Receptor Down-Regulation 20 Discordance Between in vivo and in vitro T Cell Responsiveness 21 Conclusion 23 References 24

6 Contents VI Pathways and Regulation of B-Cell Responsiveness and Tolerance Scott, D.W. (Rochester, Ν.Υ.); Warner, G.L. (Syracuse, Ν.Υ.); Vai, X.; Kent, S.C. (Rochester, N.Y.) 34 Historical Overview 34 The Need for B-Cell Tolerance 34 Models of B-Cell Tolerance 35 Anti-IgM as a Surrogate for Antigen 35 Neonatal Depletion 36 Adult B-Cell Tolerance with Anti-Ig 38 Positive versus Negative Signaling 38 Role of Cytokines in Preventing Tolerance 39 Differential Roles of IgM and IgD 40 Are CDS + B Cells Sensitive to Tolerance Induction 41 Fate of Hapten-Specific B Cells in Tolerance 42 Role of B-Cell Maturational Stage 42 Importance of the Carrier 43 Transgenic Mice in the Analysis of Tolerance 44 Lysozyme versus H-2: Anergy and Deletion 44 Lysozyme Transgenics 44 H-2 Transgenics 46 Naptens, DNA and Other Epitopes 47 A Cautionary Note on B-Cell Subsets in Transgenic Mice 49 B-Lymphoma Models for Tolerance 50 Cell Cycle Control by Oncogenes, Cyclins and the Retinoblastoma Gene Product, prb 50 Role of c-rye and TGF-β in Cell Cycle Control: Overview 52 Regulation of Cell Growth by c-rye and Aπti-IgM in B-Cell Lymphomas 53 Analysis of Signal Transduction Pathways in B-Cell Tolerance 55 The Ig Complex and Second Messengers 55 Co-Stimulation: Why Do We Need T Cells? 58 Acknowledgements 59 References 59 Regulation of B Cell Tolerance and Triggering by Immune Complexes Fedyk, E.R.; Borrello, M.A.; Brown, D.M.; Phipps, R.P. (Rochester, N.Y.) Introduction 67 Factors Which Influence the Development of Immune Complexes 68 Immune Complex Interaction with B Lymphocytes 70 Tolerance in the B Cell Repertoire Involves Two Mechanisms 73 Clonal Deletion versus Clonal Anergy 73 Models of B Cell Unresponsiveness Mediated by Immune Complexes and Fc Receptors 74 Immune Complex Induction of Unresponsiveness in vivo 74 Immune Complex Induction of Unresponsiveness in vitro 75

7 Contents VII Mechanisms of Unresponsiveness 76 The Role of the Fc Receptor 76 Signaling through sig and the FcR 77 Effect of the Macrophage Product Prostaglandin Ε2 on Immune-Complex-Induced Unresponsiveness 78 Immune Complexes Inhibit Only Some Aspects of B Cell Responsiveness 79 Induction of Antibody Secretion by Immune Complexes 80 Immune Complexes and IFN-y Promote Hapten-Specific IgG2a Secretion 81 PGΕ2 Potentiates IFN-y, but not Immune Complex and IFN-y Induction of Hapten- Specific IgG2a Production 82 camp-dependent and camp-independent Mechanisms Promoting Immune Complex- Induced FL-Specific IgG2a Production 83 Conclusion 86 Acknowledgements 87 References 87 T Cell Clonal Anergy Gilbert, K.M. (La Jolla, Calif.) 92 Introduction 92 Inducing Tolerance of Th Cells in vitro 93 Inducing Th Cell Tolerance with Naturally Tolerogenic APC 96 Tolerance of Thl and Th2 Cells in vivo 98 Examining the Mechanism for T Cell Tolerance 99 Role of Costimulator Signals in T Cell Anergy 100 Functional Consequences of T Cell Anergy 104 Molecular and Biochemical Consequences of T Cell Anergy 106 Concluding Remarks 109 References 109 Regulation of the Immune Response within Privileged Sites Ksander, B.R.; Streilein, J.W. (Miami, Fla.) 117 Introduction 117 The Fetus as an Immune Privileged Site 119 Development of the Maternal-Fetal Junction 119 Expression of Class I and II Antigens on Trophoblasts 120 Resistance of Trophoblasts to Lysis by Cytotoxic Effector Cells 121 Identification of Unique 1K-Like Cells within the Decidua 122 Role of the Local Microenvironment in Maintaining Immune Privilege 123 Anterior Chamber of the Eye 125 Induction of ACRID 126 Role of the Local Microenvironment in the Induction of ACRID 127 Role of the Local Microenvironment in the Efferent Phase of the Immune Response 128

8 Contents VIII The Brain as an Immune Privileged Site 130 The Testis as an Immune Privileged Site 133 Tumors as Immune Privileged Sites 135 Conclusions 138 References 139 Suppressor Cells and Immunity Webb, D.R. (Palo Alto, Calif.); Kraig, Ε. (San Antonio, Tex.); Devens, B.H. (Palo Alto, Calif.) 146 Historical Background 146 Demonstration of Suppressor Cells in in vivo Immune Responses 151 Role of Suppressor Cells in Infectious Disease 151 Role of Suppressor Cells in Autoimmune Disease 153 Role of Suppressor Cells in the Normal Immune Response 154 Role of Suppressor Cells in Cancer 156 Characterization of Suppressor Cells in vitro 157 Suppressor Cell Clones 157 Cytokines and Suppression 160 Antigen-Specific Suppressor Factors (TSF) 163 Use of TCR Immunoglobulín Genes by Antigen-Specific T Cells 165 Novel Approaches to Cloning the X Chain 167 Phenotypic Studies of Suppression 167 Antigen Recognition and Activation of Ts 171 Nonspecific Suppression 172 Veto Cells? 175 Conclusions 176 References 177 Topics of Clinical Interest T Cell Tolerance: Models for Clinical Application to Allergy and Autoimmunity Schad, V.C. (Waltham, Mass.) 193 The Recognition Triad 193 The Differential Outcome of Class II-Registered T Cell Activation 194 The Mechanisms of T Cell Unresponsiveness 195 Models of T Cell Tolerance 197 Tolerance to Protein Antigens 197 T Cell Tolerance in the Experimental Allergic Encephalomyelitis (EAE) Model 198 The Model of Allergic Disease 199 Conclusion 201 References 201

9 Contents IX Towards T Cell Vaccination in Rheumatoid Arthritis Laar, J.M. van; Miltenburg, A.M.M.; Breedveld, F.C. (Leiden); Cohen, I.R. (Rehovot); Vries, R.R.P. de (Leiden) 206 Introduction 206 Experimental Allergic Encephalomyelitis 207 Role of Τ Cells in the Pathogenesis of EAE 207 Role of Τ Cells in Acquired Immunity to ΕΑΕ 208 Clinical Effectiveness of TCV in ΕΑΕ 211 Adjuvant Arthritis 215 Role of Τ Cells in Pathogenesis of AA 215 Role of Τ Cells in Acquired Immunity to AA 215 Insulin-Dependent Diabetes mellitus 217 ΕΑΕ, AA and IDDM: A Common Mechanism for TCV9 218 Introduction 218 Determinants Involved in Τ-Τ Cell Recognition 219 Effector Mechanisms 219 Contribution of Other Cells 219 Extent of the Network 220 Rheumatoid Arthritis 220 Role of Τ Cells in RA 220 TCV in RA Patients: An Experimental Study 222 Differences with Animal Studies of TCV 226 Concluding Remarks 228 References 229 Mechanisms of Tolerance to Allografts Lee, R.S.; Auchincloss, H., Jr. (Boston, Mass.) 236 Introduction 236 Clonal Deletion 236 Τ Cell Clonal Deletion in the Thymus 236 B Cell Clonal Deletion 237 Clonal Anergy 237 Τ Cell Clonal Anergy 237 Anergy to Antigens Expressed Extrathymically in Transgenic Mice 239 B Cell Clonal Anergy 240 Suppression 241 Specific Suppression 241 Natural Suppressor (NS) Cells 242 Veto Cells 242 Strategies to Achieve Tolerance to Allografts 242 Bone Marrow Transplantation (BIT) 242 Intrathymic Injection 244 Chimerism Following Organ Transplantation 245

10 Contents X Peripheral Tolerance Induction by Intravenous Injection of Donor Cells 245 APC Depletion and Modification 245 Monoclonal Antibodies 246 Conclusion 246 References 247 Oral Tolerance: A Biologically Relevant Pathway to Generate Peripheral Tolerance against External and Self Antigens Friedman, A.; Al-Sabbagh, A.; Santos, L.M.B.; Fishman-Lobell, J.; Polanski, M.; Prabhu Das, M.; Khoury, S.J.; Weiner, H.L. (Boston, Mass.) 259 Introduction and Historical Perspectives 259 The Intestinal Immune System 260 Ontogeny 260 Structure: Anatomy, Histology and Lymphocyte Populations 262 Function: Interpretation of Immunogenic and Tolerogenic Signals 264 Mechanisms for Oral Tolerance 268 General Considerations 268 Clonal Deletion 270 Anergy 270 Suppression 271 Clinical Application of Oral Tolerance 272 Autoimmune Disease and Allergies 272 Transplantation 277 Vaccine Design 278 Summary and Conclusions 279 References 279 Mechanisms of Ultraviolet Radiation Carcinogenesis Grabbe, S.; Granstein, R.D. (Boston, Mass.) 291 Carcinogenic Effects of UVR 291 UV-Induced Neoplastic Transformation 293 Subcellular Targets for Carcinogenic Effects of UVR 293 UV-Induced Immunomodulation 294 UV-Absorbing Molecules Mediating the Immunomodulatory Effects of UVR 295 Relationship between UV-Induced Immunomodulation and Carcinogenesis 296 Epidemiological Data 296 Cellular and Soluble Mediators Involved in UV-Induced Modulation of Tumor Immunity 296 Modulation of Cutaneous Antigen Presentation by UVR 299 Tumor Antigen Presentation by Epidermal APC 302 References 304

11 Contents XI Regulation of Immunity by Ultraviolet Radiation and Photosensitized Reactions Perez, M.I.; Edelson, R.L. (New Haven, Conn.) 314 Medium-Wave Ultraviolet Light 314 Long-Wave Ultraviolet Radiation and Psoralens 319 Other Photosensitizing Reactions 322 Conclusion 323 Note Added in Proof 323 References 323 Subject Index 331

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13 Preface The revolution in biology of the past two to three decades has led to a dramatic increase in our understanding of immune processes. It is now recognized that the immune response represents the activity of an enormous web of interacting cells and humoral factors. Furthermore, the importance of intracellular signalling in these processes is now appreciated as is the role in immune responses of cells, such as keratinocytes and endothelial cells (amongst others), not usually thought of as immunologically relevant. These insights have led both to major advances in the basic molecular and cellular biology of the immune response and also have important implications for clinical immunology. The purpose of this volume is to present the current understanding of physiologic mechanisms of immune regulation along with the impact of this knowledge on selected clinical questions. Reviewed within this volume are such topics as T- and B-cell tolerance (including neonatal tolerance, clonal anergy and the role of immune complexes in tolerance), clonal deletion, suppressor cells, mechanisms of immune privileged sites, and experimental models of tumor immunity. The possible utility of manipulating the immune response for therapeutic benefits is explored in contributions discussing oral tolerance, ultraviolet radiation and photosensitized effects on immunity, T-cell vaccination and regulation of immunity with T-cell epitopes. Thus, our understanding of the regulation of the immune response has advanced dramatically in recent years. Of perhaps greater importance, this work has led to new approaches for the understanding and treatment of disease. Hopefully, the reader will find the fascinating articles in this issue of Chemical Immunology to be informative, useful and stimulating.

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