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

被引:80
作者
Wen, L
Wong, FS
Tang, J
Chen, NY
Altieri, M
David, C
Flavell, R
Sherwin, R
机构
[1] Yale Univ, Sch Med, Dept Internal Med, Endocrinol Sect, New Haven, CT 06520 USA
[2] Yale Univ, Sch Med, Immunobiol Sect, New Haven, CT 06520 USA
[3] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA
[4] Mayo Clin, Dept Immunol, Rochester, MN 55905 USA
关键词
type; 1; diabetes; animal model; human MHC molecules; transgenic mice;
D O I
10.1084/jem.191.1.97
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 beta 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 gamma, 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 (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(+)/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.
引用
收藏
页码:97 / 104
页数:8
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