In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (HLA)-DQ Molecules to the Development of Diabetes

doi:10.1084/jem.191.1.97

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© The Rockefeller University Press, 0022-1007/2000/1/97/ $5.00
The Journal of Experimental Medicine, Volume 191, Number 1, January 3, 2000 97-104

Original Article

In Vivo Evidence for the Contribution of Human Histocompatibility Leukocyte Antigen (HLA)-DQ Molecules to the Development of Diabetes

Li Wen^a, F. Susan Wong^b, Jie Tang^a, Ning-Yuan Chen^a, Martha Altieri^a, Chella David^d, Richard Flavell^b,c, and Robert Sherwin^a
^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

Correspondence to: Li Wen, Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, Box 208020, New Haven, CT 06520. Tel:203-785-7186 Fax:203-737-5558 E-mail:li.wen{at}yale.edu.

Although DQA1*0301/DQB1*0302 is the human histocompatibilityleukocyte antigen (HLA) class II gene most commonly associatedwith human type 1 diabetes, direct in vivo experimental evidencefor its diabetogenic role is lacking. Therefore, we generatedC57BL/6 transgenic mice that bear this molecule and do not expressmouse 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 expressingcostimulatory molecule B7-1 on ß cells (which normallydo not develop diabetes), 81% of the DQ8⁺/mII^-/B7-1⁺ mice developedspontaneous diabetes. The diabetes was accompanied by severeinsulitis 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 theputative islet autoantigens, insulin and glutamic acid decarboxylase(GAD). Diabetes could also be adoptively transferred to irradiatednondiabetic DQ8⁺/mII^-/B7-1⁺ mice. In striking contrast, noneof the transgenic mice in which the diabetes protective allele(DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouseMHC class II molecules but remained for the expression of B7-1on pancreatic ß cells (DQ6⁺/mII^-/B7-1⁺) developed diabetes.Only 7% of DQ^-/mII^-/B7-1⁺ mice developed diabetes at an olderage, 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 provokesautoimmune diabetes in non–diabetes-prone rat insulinpromoter (RIP).B7-1 C57BL/6 mice. Our data provide direct invivo evidence for the diabetogenic effect of this human MHCclass II molecule and a unique "humanized" animal model of spontaneousdiabetes.

Key Words: type 1 diabetes, animal model, human MHC molecules, transgenicmice

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