In recent years, transplantation immunologists working with NOD mice have discovered that they have unusual features besides their development of diabetes. NOD mice are highly resistant to tolerance induction by several different approaches, even for skin grafts and heart transplants. NOD mice also have an unusually powerful capacity to reject allografts entirely through the indirect pathway. The experiments proposed in this application will explore the hypothesis that the development of autoimmunity in NOD mice and their unusual transplantation traits have a common etiology involving abnormalities of their peripheral T cell regulatory mechanisms. In the first Specific Aim we will determine the genetic basis for the resistance of NOD mice to tolerance induction and for the unusual strength of their indirect effector response. These experiments will use a classical immunogenetics approach to determine whether the two transplantation traits of NOD mice have a common genetic basis and whether it involves diabetes susceptibility genes. In the second Specific Aim we will use in vitro experiments to explore the mechanisms responsible for the resistance of NOD mice to tolerance induction and for the unusual strength of their indirect effector response. These experiments will determine whether disordered peripheral regulatory mechanisms are responsible for the transplantation traits as well as the tendency of NOD mice to develop autoimmunity. In the third Specific Aim we will perform in vivo experiments designed to explore the mechanisms responsible for the NOD transplantation traits and to overcome their resistance to tolerance induction and the unusual strength of their indirect effector response. Part of the purpose of these experiments is to identify therapies that might be used for patients who might be identified as having the genes responsible for the NOD transplantation phenotype.