Experimental autoimmune diabetes:: A new tool to study mechanisms and consequences of insulin-specific autoimmunity

(Prepro)insulin is considered a central antigenic determinant in diabetic autoimmunity. Insulin has been used to modify diabetes development in NOD mice and prediabetic individuals. We have recently shown that (prepro)insulin can adversely promote diabetes development in murine type 1 diabetes. Based on these findings we have developed experimental autoimmune diabetes (EAD), a new mouse model characterized by (1) CD4(+)/CD8(+) insulitis, induced by (2) (prepro)insulin DNA vaccination, leading to (3) beta cell damage and insulin deficiency in (4) RIP-B7.1 transgenic mice (H-2b). EAD develops rapidly in 60-95% of mice after intramuscular, but not intradermal ("gene gun"), vaccination; and DNA plasmids expressing insulin or the insulin analogues glargine, aspart, and lispro are equally potent to induce EAD. Similar to NOD mice, diabetes is adoptively transferred into syngeneic recipients by spleen cell transplantation in a dose-dependent fashion. We have devised a two-stage concept of EAD in which T cell activation and expansion is driven by in vivo autoantigen expression, followed by islet damage that requires beta cell expression of costimulatory B7.1 for disease manifestation. Taken together, EAD is a novel, genetically defined animal model of type 1 diabetes suitable to analyze mechanisms and consequences of insulin-specific T cell autoimmunity.