Immunoregulatory Mechanisms in the Rheumatic Disease

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EXCEED THE SPACE PROVIDED. Systemic lupus erythematosus is an autoimmune disease manifested by polyclonal B cell activation with numerous autoantibodies and many T cell defects. While all recognize the importance of immune regulation in preventing autoimmunity, and that certain T cells develop this capacity, progress in delineating the development and mechanism of action of regulatory T cells has been slow. We have accumulated considerable evidence that transforming growth factor-beta (TGF- ) has a crucial role in the induction of regulatory T cells and that lymphocyte production of this cytokine is decreased in human SLE. The principal goal of this proposal is to generate potent regulatory T cells ex-vivo and demonstrate that the adoptive transfer of these cells can alter the course of mouse lupus. We will also determine the optimal composition of regulatory T cells for adoptive transfer, elucidate reversible defects of regulatory cell differentiation in SLE, and learn whether these regulatory T cells can be expanded. There are five specific aims. The first two will be performed with Dr. Bevra Hahn and her group at UCLA. Hahn's laboratory has been comparing the T cell response of the lupus (NZB x NZW) Fl mice with the MHC identical normal (BALB/c x NZW) Fl mice. The first aim is to generate CD4+ and CD8+ regulatory T cells ex-vivo from the normal C/WF1 mice and show that the adoptive transfer of these cells decreases nephritis and increases survival of female B/WF1 mice. The second aim will be to accomplish this goal using T cells from affected B/WF1 mice. The third aim is to prevent the development of a lupus-like syndrom which can be induced in mice with normal genetic background. The fourth aim is to determine the molecular events how TGF- induces naive T cells to develop potent regulatory activity and to elucidate the mechanism of action of these cells, disease. In aim five we characterize specific defects in the generation of regulatory T cells in mouse and human SLE, determine whether these defects can be corrected by exposure to the appropriate cytokines, and whether the resulting suppressor effector cells can be expanded. . This proposal will serve as the foundation for a novel treatment for patients with SLEand possibly other autoimmune diseases that, if successful, would avoid the toxic side effects of the present generation of therapeutic agents. PERFORMANCE SITE ========================================Section End===========================================