Six NOD-derived genomic intervals have been identified and introduced into C57Bl/6 congenic strains. Each of these intervals contains a locus contributing to diabetes susceptibility in the NOD, and the congenic strains will be inter-crossed to produce a collection of polycongenic strains containing various combinations of these NOD-derived intervals. Each strain will be assessed for insulitis, IDD susceptibility, and the expression of a variety of IDD-associated autoimmune phenotypes including the production of autoantibodies specific for GAD and insulin. Pathologic properties of each polycongenic strain that develops either spontaneous or cyclophosphamide-induced IDD will be studied to test the hypothesis that susceptibility is inherited as a threshold liability in which multiple distinct combinations of susceptibility alleles can result in IDD and insulitis. Additional aims will study the role of these same intervals in modulating autoimmunity by bone marrow reconstitution of NOD mice with T depleted bone marrow from the polycongenic strains, and a final aim will produce additional congenic recombinants for each genomic interval to improve the map position of susceptibility loci.
