Induction of type 1 diabetes in diabetes-resistant (BB-DR) rats

Abstract

The BioBreeding - Diabetes Prone (BB-DP) rat spontaneously develops an autoimmune diabetic syndrome that is dependent on the RT1u Major Histocompatibility Complex (MHC) haplotype and homozygosity for an allele at the Lymphopenia (Lyp) locus. Lyp mutation is responsible for a peripheral T-lymphopenia. There are other genetic loci contributing to diabetes susceptibility in this strain. BB rats carrying wild-type Lyp alleles are not lymphopenic and are resistant to spontaneous diabetes (Diabe-tes Resistant [DR]). Our study shows that thymectomy and exposure to one sublethal dose of g-irradiation (TX-R) at 4 weeks of age result in the rapid development of insulitis followed by diabetes in 100% of DR rats. Administration of CD45RC CD4+ TCRab+ T cells from unmanipulated syngeneic donors immediately after irradiation prevents the disease. Splenic T cells from TX-R induced diabetic animals adoptively transfer type 1 diabetes to T-deficient recipients. WAG, WF and LEW strains are resistant to TX-R induced insulitis/diabetes. This novel model of TX-R induced diabetes in BB-DR rats can be used to identify environmental and cellular factors that are responsible for the initiation of antipancreatic autoimmunity.