Major aim of this project is to ask whether selected auto antigens inserted as transgenes in NOD mice will prevent the development of an immune response to the alleged auto antigen and thereby, block disease induction and/or perpetuation. The four specific aims are: 1. To obtain murine cDNA clones encoding the 67kd and 65kd isoforms of glutamic acid decarboxylase (GAD), carboxypeptidase H, peripherin and 65kd heat shock protein (HSP). 2. To subclone these cDNA's into an expression vector in which the murine I-E/alpha promoter, with a B-globin intron, will drive expression of the incorporated cDNA's in encoding GAD, carboxypeptidase H, perhipherin and 65kd HSP. 3. To introduce these E/alpha promoter - B-globin intron - cDNA coding sequences into NOD mouse one cell embryos to produce transgenic mice expressing the cDNA encoding the gene product in thymus, lymph nodes and spleen. 4. To determine the presence or absence of auto-antibodies to the transgenic encoded protein; the degree of immunological tolerance to this protein; and the incidence of IDDM and insulitis in male and female transgenic NOD mice and their non-transgenic littermate controls. These studies will answer an important question as to the pathophysiological role of these putative auto antigens in the development of insulitis and diabetes in NOD mice. If tolerance induction to one or more of these auto antigens block disease sequally, it would provide an interesting model for potential immunotherapy of human Type I IDDM.