Susceptibility and resistance to insulin dependent diabetes mellitus (IDDM) are linked to particular alleles of MHC class II genes. However, the specific mechanism(s) involved have not been defined. To examine the biological functions of these genes we plan to generate transgenic nonobese diabetic (NOD) mice in which the endogenous class II genes are replaced by human DQ genes. Transgenes containing the DQ8 alleles DQA1*0301/DQB*0302, which confer the highest risk for the development of diabetes in humans, will be directly coinjected into the embryos of class II deficient mice and the resulting animals will then be bred onto the diabetogenic NOD background. Using a similar strategy we will generate transgenic mice expressing the DQ6 molecule DQA1*0102, DQB*0602, which is known to confer dominant protection in humans. These transgenic NOD mice will serve as an in vivo model system for defining the functions of the HLA DQ alleles in the pathogenesis of IDDM, and will be important for other components of this program project, namely the testing of synthetic DQ8 blockers (project 1) and the identification of DQ8 T cell epitopes (project 3). The specific aims of this proposal are to: 1) generate NOD mice transgenic for human MHC genes that confer susceptibility or resistance to IDDM; 2) characterize HLA-DQ expression and function in these transgenic lines; 3) assess the development of islet cell specific autoimmunity in the HLA-DQ transgenic NOD mice and the modulation of this process by non-peptidic HLA-DQ blockers; 4) examine the early T cell response to islet cell antigens in DQ transgenic mice.