The goal of this project is to identify and characterize the earliest autoreactive T cells and antibodies in type I diabetes, both in the NOD mouse model and in humans. This will be done using a novel chemical library screening-based technology recently developed in the laboratory of the P.I. It facilitates an unbiased search for antigen-specific antibodies or T cells that are highly elevated in the blood of patients with a particular disease, but are essentially absent in matched controls. No knowledge of the antigens recognized by the antibodies or T cells is required. This effort will address several unmet critical needs in the field. For example, we will develop a simple blood test for early onset, and hopefully pre-symptomatic, type I diabetes. This would have a profound impact on the management of this disease. We will also construct a complete "history" of the different antigen-specific autoimmune reactivities that arise in the NOD mouse over time. This should contribute a great deal of fundamental knowledge regarding the molecular mechanism of disease development in the mouse and perhaps in humans as well.. Finally, we will evaluate a novel therapeutic strategy in which the activities of the autoimmune B and T cells are blocked using synthetic compounds that target the antigen- binding sites of autoantibodies and autoreactive T cell receptors. This effort will point the way to a revolutionary approach to the treatment of type I diabetes, and autoimmune diseases in general, in which the root cause of the disease is treated without the need for general immunosuppression. Thus, we believe that the successful completion of this project will have a major impact on the diagnosis, treatment and understanding of type I diabetes. PUBLIC HEALTH RELEVANCE: This project aims to identify novel antibodies and T cells involved in the progression of type I diabetes. We hope that this will lead to effective diagnostic tests for early stage disease and also set the stage for a novel therapeutic strategy in which only the autoimmune components of the immune system are targeted.