H-2D end confers dominant protection from IL-10-mediated acceleration of autoimmune diabetes in the nonobese diabetic mouse

BALB/c mice that express IL-10 as a transgene in their pancreatic beta cell s (Ins-IL-10 mice) do not develop diabetes, even after crossing to nonobese diabetic (NOD) mice ((Ins-IL-10 x NOD)F-1 mice). However, backcross of F-1 mice to NOD mice (NOD.Ins-IL-10 mice) results in N2 and N3 generations tha t 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-is let infiltration and preserved beta cell function. Moreover, expression of I-A(d) and I-E-d MHC class II molecules of BALB/c origin was not responsibl e 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 develo pment of accelerated diabetes, we generated transgenic mice expressing D-d under the control of the MHC class I promoter. We found that double transge nic NOD.Ins-IL-10-D-d mice developed accelerated diabetes in a fashion simi lar to NOD.Ins-IL-10 mice that were D-d negative. Microsatellite analysis o f 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 co ntrol of H-2D(d)-linked gene(s) on IL-10-mediated acceleration of autoimmun e diabetes and dominant protection of the D-d region in NOD.Ins-IL-10 mice.