APOPTOSIS OF ANTIGEN PRESENTING CELLS--AUTOIMMUNITY ROLE

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I have developed my interest in autoimmunity and the pathogenesis of systemic rheumatiC disease both through my clinical training and the experience I have gained in immunology research. My immediate interest is in apoptosis and immune regulation. The proposed project will enhance my research skills and will apply state of the art techniques and approaches toward understanding the role of apoptosis and T cell:antigen presenting cell (APC) interactions in systemic autoimmunity. This experience will enable me to attain my long-term goal of becoming an independent investigator. Dr. Elkon's laboratory has expertise in the majority of techniques needed for this project and has made significant contribution's in the fields of apoptosis and murine lupus models. The scientific environment of the Hospital for Special Surgery and the Cornell University Medical Center provides direct access to an excellent multi-institutional immunology program and allows close collaborations with investigators expert in a multitude of related fields. This environment provides the optimal situation in which to achieve my goals. The overall goal of the current proposal is to study the functional significance of APC apoptosis in normal immunoregulation and in systemic lupus erythematosus as well as to define which parameters (cytokines, activation and adhesion molecules) are required for Fas-mediated apoptosis of APCs. Aim 1 of this proposal will explore the roles of cytokines as well as macrophage cell surface activation and adhesion molecules in Fas mediated apoptosis. To study the selective effect of macrophage FasR deficiency in vivo (Aim 2), RAG/MRL/pr and RAG/MRL/++ mice will be injected with MRL/++ lymphocytes depleted of macrophages and the onset and severity of autoimmunity compared. In Aim 3, we will examine the function of Fas in dendritic cells. In Aim 4 we will extend our study to human monocytes and macrophages from normals and patients with SLE. Our studies will explore further the mechanism and functional significance of a novel immunoregulatory pathway between T cells and APCs and will expand our knowledge on the role of macrophages and dendritic cells in immunity and autoimmunity.