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H-2D End Confers Dominant Protection from IL-10-Mediated Acceleration of Autoimmune Diabetes in the Nonobese Diabetic Mouse¹

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037

BALB/c mice that express IL-10 as a transgene in their pancreatic cells (Ins-IL-10 mice) do not develop diabetes, even after crossing to nonobese diabetic (NOD) mice ((Ins-IL-10 x NOD)F₁ mice). However, backcross of F₁ mice to NOD mice (NOD.Ins-IL-10 mice) results in N2 and N3 generations that develop accelerated diabetes. In this study, we found that NOD.Ins-IL-10 mice that expressed BALB/c-derived MHC molecules (NOD.Ins-IL-10(H-2^g7/d) mice) were protected from diabetes. This protection associated with peri-islet infiltration and preserved cell function. Moreover, expression of I-A^d and I-E^d MHC class II molecules of BALB/c origin was not responsible for protection, but NOD.Ins-IL-10 mice that expressed BALB/c MHC class I D^d molecules (NOD.Ins-IL-10(H-2^g7/d) mice) did not develop diabetes. To directly test the possibility of a protective role of H-2D^d in the development of accelerated diabetes, we generated transgenic mice expressing D^d under the control of the MHC class I promoter. We found that double transgenic NOD.Ins-IL-10-D^d mice developed accelerated diabetes in a fashion similar to NOD.Ins-IL-10 mice that were D^d negative. Microsatellite analysis of H-2D^d-linked loci confirmed association between BALB/c-derived alleles and protection of NOD.Ins-IL-10(H-2^g7/d) mice. These results suggest a control of H-2D^d-linked gene(s) on IL-10-mediated acceleration of autoimmune diabetes and dominant protection of the D^d region in NOD.Ins-IL-10 mice.

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