Derivation of diabetes-resistant congenic lines from the nonobese diabetic mouse

Autoimmune diabetes is a polygenic disease process in man and rodents. To identify and characterize genes involved in the pathogenesis of diabetes in nonobese diabetic (NOD) mice, we initiated a repetitive backcross of diabetes-resistant C57L/J mice onto the NOD strain. This breeding scheme was based on the premise that selection for the trait of disease resistance among genetically mixed mice could be used to maintain transmission of nonpermissive alleles from the diabetes-resistant strain at critical diabetes susceptibility loci. Each of the three recombinant congenic mouse lines derived by this strategy retains a unique constellation of C57L/J-derived DNA segments. Consistent with the involvement of different genetic loci, the pancreatic histology of disease-resistant mice differs from that in NOD mice in a line-specific manner. Functional studies using these lines demonstrate that pathogenesis of autoimmune diabetes is a multistep process which can be blocked at a minimum of three critical, genetically determined points.