MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-I DEFICIENT NOD-B2M(NULL) MICEARE DIABETES AND INSULITIS RESISTANT

Specific allelic combinations within the class II region of the major histocompatability complex (MHC) represent a major genetic component f or susceptibility to autoimmune insulin-dependent diabetes mellitus (I DDM) in humans (1,2). We produced and used a stock of NOD/Lt mice cong enic for a functionally inactivated beta 2-microglobulin (B2m(null)) l ocus to assess whether there was an absolute requirement for MHC class I expression and/or CD8(+) T-cells in diabetogenesis. These NOD-B2m(n ull) mice do not express cell surface MHC class I molecules or produce detectable levels of CD8(+) T-cells and are diabetes and insulitis re sistant. Previous results from transgenic mouse models indicated that intracellular accumulation of MHC class I molecules negatively affects pancreatic p-cell function and can result in the development of nonau toimmune insulin-dependent diabetes mellitus (IDDM). MHC class I molec ules have been shown to accumulate intracellularly in the presence of a disrupted B2m locus, but this mutation does not negatively affect pl asma insulin levels in either NOD/Lt mice or in those of a mixed 129 a nd C57BL/6 genetic background. Interestingly, 14% of the male mice in this mixed background did develop hyperinsulinemia (>1,500 pM) indepen dent of the disrupted B2m locus, suggesting that these mice could conc eivably develop insulin-resistant diabetes. However, none of these mic e became diabetic at up to 22 months of age. Thus, elimination of cell surface MHC class I expression with a disrupted B2m gene blocks autoi mmune diabetes in NOD/Lt mice, without engendering a separate, distinc t form of glucose intolerance.