Main description:

It has been a challenge for us to edit this volume of Endocrinology and Metabo lism: Progress in Research and Clinical Practice. The topic of the pathogenesis of insulin-dependent, type I diabetes mellitus is particularly appropriate for this series, since advances in this area have been made, to a large extent, by applying state-of-the-art laboratory techniques to clinical samples. Over the last several years, a number of lines of evidence have been gathered, suggesting that classic type I diabetes mellitus results from the autoimmune des truction of pancreatic beta-cells in genetically susceptible individuals. This hypothesis is particularly appealing because it offers a rational approach to the prevention of diabetes by immunosuppression. We have tried to present a balanced, authoritative summary of the information currently available to support the autoimmune hypothesis for the pathogenesis of human type I diabetes, to place this information in historical perspective, to include relevant information from animal models of type I diabetes in which more invasive experimentation is ethical, and, finally, to update the reader on the current status of attempts to intervene in the progression of diabetes with immunosuppressive drugs. New York, New York Fredda Ginsberg-Fellner Robert C. McEvoy Contents Preface.. . . .. .. .. . . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . .. . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xl . . . . . . . . . . . . . 1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present . . . . . . . . . . . . ..................... . . . . . .

Contents:

1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present.- Autoimmunity.- The Concept of IDDM as an Autoimmune Disease.- The Association Between IDDM and HLA.- Etiologic Factors with Implications for the Pathogenesis of IDDM.- The Autoantigen in IDDM.- Presentation of Autoantigen.- Autoantigen Recognition in IDDM.- The Effector Phase in IDDM.- Conclusion.- 2. Immunogenetics and the Pathogenesis of Insulin-Dependent Diabetes Mellitus.- Genetic Background.- Environmental Factors.- Speculations on the Mechanism of IDDM Pathogenesis.- 3. Association of Insulin-Dependent Diabetes Mellitus and Other Autoimmune Diseases.- IDDM and Thyroid Autoimmunity.- Other Endocrinopathies Associated with Type 1 Diabetes Mellitus.- How Does Autoimmune Disease Develop?.- Can Autoantibodies Affect More Than One Gland? Are They Mono- or Polyclonal?.- Summary and Conclusions.- 4. The Humoral Anti-Islet Immune Response: Cytoplasmic Islet-Cell Antibodies: Technical Aspects and Clinical Applications.- Assays for ICA Determination.- Approaching Standardization of the Cytoplasmic ICA Test.- Clinical Application of the ICA Test.- Synopsis, Recommendations, and Conclusions.- 5. The Humoral Anti-Islet Response: Biochemical Characterization.- Autoantigens Detected in Human Islets.- Autoantigens May Define Disease Specificity in Human Autoimmunity.- Western Blotting Analysis of Islet Autoantigens.- Analyzing Circulating Immune Complexes in Diabetes.- Summary.- 6. The Humoral Anti-Islet Immune Response: Immunochemical Studies of Glycoconjugate Antigens.- What Are Gangliosides?.- Immunochemical Characterization of Monoclonal Antibody-Defined, Islet-Cell Antigens.- Immunochemical Properties of the Autoantigen(s) of Pancreatic Islets.- Extraction and Partial Purification of the ICA Glycolipid Antigen.- Glycolipid Antigens in Animal Models of Type I Diabetes.- Multiplicity of Antigens in Humoral Autoimmunity of Type I Diabetes.- Monoclonal Antibody-Defined, Islet-Cell Glycolipid Antigens.- Physiological Roles of Islet-Cell Gangliosides.- Antibodies to Glycolipids in Diseases Other than Type I Diabetes Mellitus.- Immunogenicity of Glycolipids.- T-Cell Reactivity to Glycolipid Antigens.- Final Comments.- 7. Insulin Autoantibodies.- 8. Cell-Mediated Anti-Islet-Cell Immune Response: Clinical Experience and Lessons from Animal Models.- Cell-Mediated, Anti-Beta-Cell Autoimmunity in Human Diabetes.- Diabetes Induced by Multiple, Subdiabetogenic Doses of Streptozotocin.- Diabetes in the Bio-Breeding Rat.- Diabetes in Nonobese Diabetic Mice.- Summary and Conclusions.- 9. The Pathogenesis of Immunologically Mediated Diabetes.- Mechanism of the Disease Process.- Disease Recurrence Model.- Disease Recurrence in Islet Grafts is CD4 T-Cell Dependent.- Free Radical Involvement in the Disease Process.- Disease Recurrence in the Grafted Tissue: A Summary.- Lessons from Fetal Pancreas Transplantation.- Effect of Cyclosporine on Disease Recurrence.- 10. Viral Pathogenesis of Insulin-Dependent Diabetes Mellitus.- Direct Cytolytic Viral Infection of Beta-Cells.- Association of Virus Infection with Autoimmune IDDM.- Persistent Infection of Pancreatic Beta-Cells and Mild Hyperglycemia.- Conclusion.- 11. Immune Intervention in Diabetes: State of the Art and Future Directions.- Experimental Immunotherapy in IDDM of Recent Onset.- Open Studies of Immunomodulatory Therapies in IDDM.- Randomized Control Trials of the Effects of Cyclosporin in IDDM.- Efficacy and Safety of Immunosuppression in Remission Induction in IDDM.- Timing of Immunomodulatory Interventions in IDDM.- IDDM in Remission: Endocrine Metabolic Status and Its Possible Implications.- Strategies for Continuing Studies of Immunotherapy in IDDM.- Summary and Conclusions.