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

Li Wen, F. Susan Wong, Jie Tang, Ning Yuan Chen, Martha Altieri, Chella David, Richard Flavell, Robert Sherwin

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Abstract

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type I 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 γ, 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.

Original languageEnglish (US)
Pages (from-to)97-104
Number of pages8
JournalJournal of Experimental Medicine
Volume191
Issue number1
DOIs
StatePublished - Jan 3 2000

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Keywords

  • Animal model
  • Human MHC molecules
  • Transgenic mice
  • Type 1 diabetes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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