Susceptibility to insulin dependent diabetes (IDD) is inherited thus, understanding the immunogenetics of autoimmune beta red cell destruction becomes critical to strategies aimed at preventing IDD. Disease prevention is the most logical approach to avert the high mortality and morbidity of IDD in man. Therefore, the long-term objective of this proposal is to identify the specific major histocompatibilty complex-associated gene(s) that provides susceptibility to IDD. The inherited susceptibility to IDD will be studied in the nonobese diabetic (NOD) mouse, which serves as an excellent model for human IDD. The MHC-associated IDD susceptibility gene in the NOD mouse has been termed Idd-ls. The specific aim of this proposal is to determine whether Idd-ls is ABNOD, which is unique by both restriction fragment length polymorphism and cDNA sequence analyses. IANOD is also distinguishable from all other IA molecules studied to date by primed lymphocyte typing and monoclonal antibody immunoreactivity, while NOD mice fail to express an IE molecule. To determine the the specific influence of ABNOD on IDD susceptibility, NOD mice, containing all IDD susceptibility genes, NOD.GD congenic mice lacking Idd-ls (the expressed gd haplotype differs from the NOD haplotype only at AB), and NOD.GD mice transgenetically reconstituted with the cloned NOD AB gene (designated NOD.GD+ABNOD mice) will be compared for development of insulitis/IDD. If ABNOD is Idd-ls, NOD.GD mice will display only mild insulitis and will not develop IDD. NOD.GD+A8NOD mice will display a greater severity of insulitis than NOD.GD mice, and some NOD.GD+AB mice may develop IDD. If ABNOD is Idd-ls, the development of strategies designed to prevent IDD might include intensified studies of MHC class II gene function in indiviuals with IDD as compared to controls.