Type 1 diabetes is a polygenic autoimmune disease in man and the NOD mouse. The genes in the MHC region are the most important in determining susceptibility or resistance to type 1 diabetes. Replacement (homologous recombination) of the NOD MHC class I K region with the R209 MHC class I K region prevented the development of diabetes and insulitis in the intra-MHC recombinant NOD mice. Similarly the replacement of the region of the NOD A, E and D with that of the R209 prevented the development of diabetes and insulitis. The investigators have established six congenic NOD lines with a homozygous segment of r209/r209 in the region of within 6.6 cM centromeric to the Lmp2-hotspot, and two congenic lines with a homozygous segment of r209/r209 in the region of within 3.3 cM from the centromere. Their observation suggests that in addition to the MHC class II A there are three more MHC-linked type 1 diabetogenic genes, two in the region of within 1.1 cM centromeric to the Lmp2 -hotspot, and one in the region of within 3.3 cM from the centromere outside the MHC. One of the first two diabetogenic genes may be the MHC class I K gene itself, otherwise they may be two non-MHC genes in the region. Their proposed studies aim to further restrict the regions including the MHC-linked diabetogenic genes: 1. To see whether the MHC class I K itself is diabetogenic. (1) Establish and screen N3 transgenic NOD mice expressing the MHC class I Kr209(wm7) for the development of diabetes. (2) Histological examination of insulitis and expression of the MHC class I Kr209(wm7) molecules in the N3 transgenic NOD mice (3) Interaction of the transgene Kr209 with the intrinsic r209/r209 chromosomal segment in the congenic line G in the development of diabetes and insulitis 2. To further narrow the region of within 1.0 cM centromeric to K (Iddla), within 1.1 cM centromeric to K(Idd1b) and the region of within 33 cM from the centromere outside the MHC region (Iddlc) to <1.0 cM. (1) Create new recombinant mice by mating the congenic line C with NOD mice for Iddla and Iddlb (2) Create new recombinant mice by mating the congenic line G with NOD mice for Iddlc
