Rodent models with spontaneous development of insulin-dependent diabetes mellitus share many features typical for human type 1 diabetes mellitus (T1DM) and have been extremely helpful in identifying etiological and pathophysiological aspects of autoimmune diabetes. The LEW.1AR1/Ztm-iddm rat is a new T1DM animal model. It arose through a spontaneous mutation in a congenic Lewis rat strain with a defined MHC haplotype (RTI.A a B/Du Cu ). This new model is of significant interest because it appears to closely parallel the human disease. In particular this new rat model shows no inherited defects of the immune system. However, detailed knowledge is essential so that this new strain can be well utilized in experimental diabetes research world-wide. In particular information on the pathophysiology, the autoimmunity and the genetics has been requested by the scientific community. We therefore aim at characterizing the new LEW.1AR1/Ztm-iddm rat in this project to such an extent that it can be offered as a defined T1DM animal model to the international scientific community complementary to the existing animal models of T1DM. The following three major aims should be addressed: A. Characterization of the autoimmune process to analyze the time course of the autoimmune process during the pre-diabetic phase, both with respect to the initiation of the apoptotic process of beta cell destruction and islet infiltration, ultimately leading to the manifestation of an overt diabetic state. B. Proof of the autoimmune nature of the diabetic syndrome through adoptive transfer to demonstrate the autoimmune nature of the diabetic syndrome in this new animal model through detailed adoptive transfer studies with selected T cell subpopulations. C. Analysis of the genetic locus responsible for the insulin-dependent diabetes mellitus to identify the locus which could be associated either with a MHC class II region expressing a mutated rather than a """"""""standard"""""""" u-haplotype, or with a mutated immunologically active regulatory locus unrelated to the major histocompatibility complex (MHC). Identification of the key elements of the genetics and pathogenesis of beta cell destruction in this new animal model of autoimmune diabetes will provide the basis for the development of novel therapeutic strategies for the prevention and cure of T1DM in humans. The characterization as proposed in this application will allow the proper use of this new T1 DM rat model for this purpose by the scientific community world-wide.
