I-E+ NONOBESE DIABETIC MICE DEVELOP INSULITIS AND DIABETES

The development of type I diabetes in the nonobese diabetic (NOD) mous e is under the control of multiple genes, one or more of which is link ed to the major histocompatibility complex (MHC). The MHC class II reg ion has been implicated in disease development, with expression of an I-E transgene in NOD mice shown to provide protection from insulitis a nd diabetes. To examine the effect of expressing an I-E+ or I-E- non-N OD MHC on the NOD background, three I-E+ and three I-E- NOD MHC congen ic strains (NOD.H-2i5, NOD.H-2k, and NOD.H-2h2, and NOD.H-2h4, NOD.H-2 i7, and NOD.H-2b, respectively) were developed. Of these strains, both I-E+ NOD.H-2h2 and I-E- NOD.H-2h4 mice developed insulitis, but not d iabetes. The remaining four congenic strains were free of insulitis an d diabetes. These results indicate that in the absence of the NOD MHC, diabetes fails to develop. Each NOD MHC congenic strain was crossed w ith the NOD strain to produce I-E+ and I-E- F1 mice; these mice thus e xpressed one dose of the NOD MHC and one dose of a non-NOD MHC on the NOD background. While a single dose of a non-NOD MHC provided a large degree of disease protection to all of the F1 strains, a proportion of I-E+ and I-E- F1 mice aged 5-12 mo developed insulitis and cyclophosp hamide-induced diabetes. When I-E+ F1 mice were aged 9-17 mo, spontane ous diabetes developed as well. These data are the first to demonstrat e that I-E+ NOD mice develop diabetes, indicating that expression of I -E in NOD mice is not in itself sufficient to prevent insulitis or dia betes. In fact, I-E- F1 strains were no more protected from diabetes t han I-E+ F1 strains, suggesting that other non-NOD MHC-linked genes ar e important in protection from disease. Finally, transfer of NOD bone marrow into irradiated I-E+ F1 recipients resulted in high incidences of diabetes, indicating that expression of non-NOD MHC products in the thymus, in the absence of expression in bone marrow-derived cells, is not sufficient to provide protection from diabetes.