In vivo evidence for the contribution of human histocompatibility leukocyte antigen (HLA)-DQ molecules to the development of diabetes

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte anti gen (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 a nd do not express mouse major histocompatibility complex (MHC) class II mol ecules (DQ8(+)/mII(-)). They did not develop insulitis or spontaneous diabe tes. However, when DQ8(+)/mII(-) mice were bred with C57BL/6 mice expressin g costimulatory molecule B7-1 on beta cells (which normally do not develop diabetes), 81% of the DQ8(+)/ mII(-)/B7-1(+) mice developed spontaneous dia betes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4(+) and CD8(+)) and B cells. T cells from the diabetic mice secre ted large amounts of interferon gamma, but not interleukin 4, in response t o DQ8(+) islets and the putative islet autoantigens, insulin and glutamic a cid decarboxylase (GAD). Diabetes could also be adoptively transferred to i rradiated nondiabetic DQ8(+)/mII(-)/B7-1(+) mice. In striking contrast, non e of the transgenic mice in which the diabetes protective allele (DBA1*0103 /DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic beta cells (DQ6(+)/m II(-)/B7-1(+)) developed diabetes. Only 7% of DQ(-)/mII(-)/B7-1(+) mice dev eloped diabetes at an older age, and none of the DQ(-)/mII(+)/B7-1(+) mice or DQ8(+)/mII(-)/B7-1(+) mice developed diabetes. In conclusion, substituti on 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 uniq ue "humanized" animal model of spontaneous diabetes.