Immune Regulation and Immunotherapy in Autoimmune Disease (eBook)

Preface 5
Contents 8
Contributors 11
Immune Regulation and Autoimmune Disease 15
Autoimmune Response and Immune Tolerance 16
1 Introduction 16
2 Thymic Selection of the Self-Reactive Repertoire 16
3 Peripheral Mechanisms of Tolerance 21
4 Conclusion 27
References 27
Priming Regulatory T Cells and Antigen- Specific Suppression of Autoimmune Disease 33
1 Summary 33
2 Introduction 33
3 Identification of T Cells With Suppressor Function 34
4 Immunotherapeutic Strategies to Treat Autoimmune Disease 37
5 Antigen-Presenting Cells and Priming of Treg 41
6 Conclusion 43
References 44
Peripheral T Cell Regulation and Autoimmunity 49
1 Introduction 49
2 Biological and Clinical Impact of Immunoregulation 50
3 Suppressor Cell Subsets 54
4 Affinity/Avidity Model of Peripheral T Cell Regulation 60
References 62
Anti-Ergotypic Regulation of the Immune Response 69
1 Introduction 69
2 Anti-Ergotypic Response 70
3 Overlap and Interactions With Other Regulatory Populations 74
4 Conclusions 75
References 77
How B Cells Contribute to Multiple Sclerosis Pathology 79
1 Introduction 79
2 B Cell Development and Activation 80
3 B Cells in Autoimmunity 81
4 B Cells in Multiple Sclerosis 82
5 B Cell Antigen Target Discovery 86
6 B Cells at the Site of Myelin Destruction: CSF and the CNS Tissue 87
7 B Cell-Directed Therapy for MS 92
8 Conclusion 93
References 93
Molecular Basis for Induction of Tolerance in Type 1 Diabetes 100
1 Introduction 100
2 Maintenance and Loss of Tolerance to ß Cell Autoantigens 101
3 Approaches to Restore Self-Tolerance to ß Cell Antigens 109
4 Conclusion 119
References 119
Co-stimulation Regulation of Immune Tolerance and Autoimmunity 134
1 Introduction 134
2 Regulation of T Cell Tolerance and Autoimmunity by ICOS and B7h 136
3 Regulation of T Cell Tolerance by PD-1 and Its Ligands 139
4 B7-H3, B7S1, and BTLA 144
5 Conclusion 145
References 147
Invariant NKT Cells and Immune Regulation in Multiple Sclerosis 152
1 Introduction 152
2 Invariant NKT Cells 153
3 Invariant NKT Cells and Autoimmune/Inflammatory Disease Models 155
4 iNKT Glycolipid Ligands and Autoimmune Disease Models 156
5 Human iNKT Cells 157
6 Analyzing iNKT Cells in Human Diseases 157
7 iNKT Cells Are Reduced in MS 159
8 CD4+ iNKT Cells Are Th2 Biased in Remission of MS 159
9 Implications and Future Research 160
References 161
CD4+CD25+ Regulatory T Cells in Autoimmune Disease 165
1 A Need for Regulation 165
2 Discovery and Rediscovery of Regulatory/Suppressor T Cells 166
3 Identifying a Regulatory T Cell 167
4 Origin and Specificity of CD4+CD25+ Treg Cells 170
5 Mechanisms of Regulation 171
6 Target Populations of Treg Cells 174
7 Clinical Relevance 175
8 Conclusion 179
References 179
Immunopathogenesis of Multiple Sclerosis: Overview 184
1 Introduction 184
2 Genetic Factors Influencing MS Susceptibility 185
3 Environmental Factors Contributing to MS Risk 185
4 Autoimmunity as the Pathogenic Effector 186
5 Interaction of Genes, Environment, and Autoimmunity 186
6 Immune Surveillance of the CNS 187
7 Immunology of MS 188
8 Immunopathogenetic Concept 193
References 194
Viral Infection and Multiple Sclerosis 201
1 Introduction 201
2 Multiple Sclerosis 202
3 Making a Viral Association 208
4 Viruses Implicated in Multiple Sclerosis 208
5 Human Herpesvirus-6 and Multiple Sclerosis 212
6 Conclusion and Future Directions 218
References 219
Multiple Sclerosis Pathology During Early and Late Disease Phases: Pathogenic and Clinical Relevance 227
1 Introduction 227
2 MS Lesions in Relation to Lesion Activity and Disease Duration 228
3 Complex Role of Inflammation in MS 234
4 Oligodendrocyte Pathology and Remyelination in Relation to Lesion Activity and Disease Phase 252
5 Axonal Pathology and Mechanisms of Injury During Early and Late Disease 256
6 Gray and Nonlesional White Matter Pathology in MS 260
7 Inflammation/Neurodegeneration Paradox: Why Does It Exist in MS? 263
8 Conclusions 265
References 266
CD8+ T Cells in Multiple Sclerosis 278
1 Genetic Basis for an Association of MS With Different T Cell Subsets 278
2 Evidence from Animal Models of MS for Contributions by Different T Cell Subsets 279
3 Clinical Trials Emphasizing a Possible Role of CD8+ T Cells in MS Patients 281
4 CD8+ T Cell Infiltration in MS Lesions 282
5 Preferential Clonal Expansion of CD8+ T Cells in MS 282
6 MHC Class I Expression in the CNS 284
7 Cytotoxic Response of CD8+ T Cells on CNS Resident Cells 286
8 Peripheral Activation of Autoreactive CD8+ T Cells 286
9 Mechanisms of CD8+ T Cell Infiltration of the CNS 288
10 Reactivation of Autoreactive CD8+ T Cells in the CNS 289
11 Proteins and Epitopes Recognized by Autoreactive CD8+ T Cells in the CNS 289
12 Conclusions and Perspective 290
References 291
Novel Immunotherapeutic Strategies and Emerging Treatments 299
Review of Novel Immunotherapeutic Strategies for MS 300
1 Introduction 300
2 Immunopathogenetic Rationale for Strategies in MS 302
3 Novel Immunotherapeutic Strategies 304
4 Neuroprotection and ÏNeurorepairÓ 333
5 Conclusions 333
References 335
T Cell Vaccination in Autoimmune Disease 350
1 Introduction 350
2 Early TCV in Autoimmune Animal Models 352
3 Human Studies in TCV 354
4 Application of TCV to Other Autoimmune Diseases 363
5 Regulatory Mechanisms Induced by TCV 366
6 Technical Improvements 369
7 Future Directions 374
References 375
Trivalent T Cell Receptor Peptide Vaccine for Treatment of Multiple Sclerosis Targets Predominant V Genes Widely Implicated in Autoimmune Diseases and Allergy 380
1 Introduction 381
2 Development of the Peripheral T Cell Repertoire 382
3 V Gene Expression Patterns in Autoimmune Diseases and Allergy 389
4 Regulation of Autoimmunity With T Cell Receptor Peptides 403
References 411
Nonmyeloablative Stem Cell Transplantation for Multiple Sclerosis 420
1 Stem Cell Replacement Therapy 420
2 Hematopoietic Stem Cell Transplantation in Multiple Sclerosis 422
3 Conclusion 432
References 432
T Cell-Targeted Therapy for Rheumatoid Arthritis 436
1 Introduction 436
2 T Cell-Targeted Therapy by Depletion 437
3 T Cell-Targeted Therapy With Disease-Modifying Antirheumatic Drugs 438
4 T Cell-Directed Therapies With Biologicals 440
5 Clinical Experience With CTLA4Ig (Abatacept) 442
6 Experience With Alefacept 443
7 Other Approaches to Inhibiting T Cell Activation 444
8 Conclusion 444
References 445
Estrogens in the Treatment of Multiple Sclerosis 449
1 Introduction 449
2 Estrogen Treatment: Attempting to Recapitulate Pregnancy 450
3 Estrogen Treatment in Experimental Autoimmune Encephalomyelitis 453
4 Estrogen Treatment in Multiple Sclerosis 457
5 Risk/Benefit Ratio of Estrogen Treatment 460
6 Estrogen Treatment: Early Versus Late in Disease 462
7 Conclusion 464
References 464
Immune Regeneration Through Hematopoietic Stem Cell Transplantation to Restore Tolerance in Autoimmune Disease 472
1 Introduction 472
2 Treating Autoimmune Diseases With HSCT: The Underlying Hypotheses 474
3 Immunological Results from Studies on HSCT for Autoimmune Disease 478
4 Conclusions 486
References 486
Cell Transplantation of Peripherally Derived Adult Cells for Promoting Recovery from CNS Injury 491
1 Introduction 491
2 Bone Marrow-Derived Cells for Cell Therapy in CNS Disorders 491
3 Peripheral Myelin-Forming Cells 496
4 Challenges in Cell Therapy Approaches for Demyelinating Disorders 500
5 Prospects of Cell-Based Clinical Approaches 501
References 504
Multiple Sclerosis: Future Directions and Prospects 508
1 Is Multiple Sclerosis an Important Disease? 508
2 Is MS One Disease? 509
3 Is MS an Autoimmune Disease? 510
4 What is the Role of CD8 T Cells in MS? 512
5 A Role for B Cells in MS? 513
6 Which are the Target Autoantigens? 514
7 Which Factors Precipitate Onset and Relapses? 516
8 What is the Interplay of Immune Response and Neuronal Degeneration? 517
9 Immune (Dys)regulation? 518
References 521
Author Index 525
Subject Index 569