Immunopathogenesis of Type 1 Diabetes Mellitus (eBook)

Front Cover 1
Advances in Immunology 4
Copyright Page 5
Contents 6
Contributors 10
Chapter 1: Autoimmune Diabetes Mellitus-Much Progress, but Many Challenges 14
1. Models of Type 1 DM 15
2. The Histocompatibility Molecules of the Autoimmune Diabetic 16
3. The Diabetic Antigens and the Diabetogenic T Cells 16
4. The Genetics of Type 1 Diabetes 19
5. Development of New Therapies in the NOD Model Which Show Promise in Studies in Patients 20
6. Effects of Administration of Glutamic Acid Decarboxylase 65 (GAD 65) to Patients with Recent-Onset T1D 21
7. The Prospect for Trials to Prevent T1DM in Susceptible Human Populations 22
References 23
Chapter 2: CD3 Antibodies as Unique Tools to Restore Self-Tolerance in Established Autoimmunity: Their Mode of Action and Clinical Application in Type 1 Diabetes 26
1. Introduction 27
2. CD3 Antibodies as Promising Tolerance-Promoting Tools: The Proof of Concept in T1D 29
3. The Clinical Results in T1D: More than 25 Years of Effort 31
4. Why is the Effect of CD3-Antibody Based Therapy Antigen Specific and Long Lasting? 34
5. Building on the Present Clinical Experience to Improve CD3 Antibody Therapy in T1D 39
6. Conclusions 43
References 43
Chapter 3: GAD65 Autoimmunity-Clinical Studies 52
1. Introduction 53
2. GAD65 Autoimmunity in T1D 61
3. Pathogenesis of GAD65 Autoimmunity 74
4. Preclinical GAD65 Studies 77
5. Phase I GAD65 Clinical Studies 77
6. Phase II GAD65 Clinical Studies 78
7. Ongoing and Future Clinical Studies 80
8. Concluding Remarks 81
Acknowledgments 81
References 81
Chapter 4: CD8+ T Cells in Type 1 Diabetes 92
1. Introduction 93
2. MHC Class I and T1D 94
3. Autoreactive CD8+ T Cells in T1D 96
4. Antigens for Diabetogenic CD8+ T Cells in Humans 99
5. The Relative Contribution of the beta-Cell-Specific CD8+ Response to T1D 108
6. Development and Activation of Diabetogenic CD8+ T Cells 109
7. Recruitment of Diabetogenic CD8+ T Cells to Islets 117
8. Mechanisms of beta-Cell Cytotoxicity in T1D 118
9. Induction of Immunologic Tolerance in Diabetogenic CD8+ T Cells 121
10. Concluding Remarks 124
Acknowledgments 125
References 125
Chapter 5: Dysrulation of T Cell Peripheral Tolerance in Type 1 Diabetes 138
1. Introduction 139
2. The Autoimmune Process of T1D 139
3. Dysregulation of Central T Cell Tolerance in T1D 141
4. Dysregulation of Peripheral T Cell Tolerance in T1D 143
5. Summary 153
Acknowledgments 154
References 154
Chapter 6: Gene-Gene Interactions in the NOD Mouse Model of Type 1 Diabetes 164
1. Type 1 Diabetes is a Multigenic Disease 165
2. Insights into a Multigenic Disease: The NOD Mouse 166
3. Defining the Function of Alleles Altering the Frequency of T1D 174
4. Functional Studies with NOD Congenic Mice: The Combination of Protective Alleles at Idd3 and Idd5 Prevent Diabet 175
5. Review of Idd3 176
6. Review of Idd5 178
7. Genetic Complexity of Idd5: Genetic Masking and the Discovery of Idd5.3 and Idd5.4 180
8. Combining Protective Alleles at Il2/Idd3 with those from the Idd5 Subregions 181
9. Conclusion 182
Acknowledgments 183
References 183
Subject Index 190
Contents of Recent Volumes 194
Color Plates 200