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Original Article

^a Section of Endocrinology, Department of Internal Medicine, the
^b Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520
^c Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut 06520
^d Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, Box 208020, New Haven, CT 06520.203-737-5558203-785-7186

li.wen{at}yale.edu

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8⁺/mII^–). They did not develop insulitis or spontaneous diabetes. However, when DQ8⁺/mII^– mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on β cells (which normally do not develop diabetes), 81% of the DQ8⁺/mII^–/B7-1⁺ mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4⁺ and CD8⁺) and B cells. T cells from the diabetic mice secreted large amounts of interferon , but not interleukin 4, in response to DQ8⁺ islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8⁺/mII^–/B7-1⁺ mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic β cells (DQ6⁺/mII^–/B7-1⁺) developed diabetes. Only 7% of DQ^–/mII^–/B7-1⁺ mice developed diabetes at an older age, and none of the DQ^–/mII⁺/B7-1⁺ mice or DQ8⁺/mII⁺/B7-1⁺ mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non–diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique "humanized" animal model of spontaneous diabetes.

Key Words: type 1 diabetes • animal model • human MHC molecules • transgenic mice

© 2000 The Rockefeller University Press

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