Idd1 and Idd3 are necessary but not sufficient for development of type 1 diabetes in NOD mouse

Abstract Type 1 diabetes in the NOD mouse is under polygenic control, with a major susceptibility gene, Idd1 , in the major histocompatibility complex (MHC). To investigate the contribution of the NOD MHC to type 1 diabetes susceptibility, a B6.NOD- H-2 congenic strain, in which the NOD MHC was introgressed onto the genetic background of the C57BL/6 strain, was established. Despite possession of the diabetogenic MHC from the NOD mouse, none of the B6.NOD- H-2 mice developed type 1 diabetes, indicating that the NOD MHC alone is not sufficient for type 1 diabetes and that non-MHC genes are also necessary. One of the strongest non-MHC genes is Idd3 , and Il2 which encodes interleukin 2, is a candidate gene for Idd3 . To test whether a combination of the NOD MHC with the NOD allele of Il2 is sufficient for type 1 diabetes, B6.NOD- H-2 mice were crossed with C3H mice, which possess the NOD allele at Il2 , and F2 mice homozygous for NOD alleles at both the MHC and Il2 were produced. None of the F2 mice developed type 1 diabetes, suggesting that NOD alleles at MHC ( Idd1 ) and Il2 ( Idd3 ) are not sufficient for type 1 diabetes in the NOD mouse.