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

Abstract

BALB/c mice that express IL-10 as a transgene in their pancreatic β cells (Ins-IL-10 mice) do not develop diabetes, even after crossing to nonobese diabetic (NOD) mice ((Ins-IL-10 × 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-2g7/d) mice) were protected from diabetes. This protection associated with peri-islet infiltration and preserved β cell function. Moreover, expression of I-Ad and I-Ed 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 Dd molecules (NOD.Ins-IL-10(H-2g7/d) mice) did not develop diabetes. To directly test the possibility of a protective role of H-2Dd in the development of accelerated diabetes, we generated transgenic mice expressing Dd under the control of the MHC class I promoter. We found that double transgenic NOD.Ins-IL-10-Dd mice developed accelerated diabetes in a fashion similar to NOD.Ins-IL-10 mice that were Dd negative. Microsatellite analysis of H-2Dd-linked loci confirmed association between BALB/c-derived alleles and protection of NOD.Ins-IL-10(H-2g7/d) mice. These results suggest a control of H-2Dd-linked gene(s) on IL-10-mediated acceleration of autoimmune diabetes and dominant protection of the Dd region in NOD.Ins-IL-10 mice.