Mechanisms of B Cell Responses in Autoimmune Disease

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DESCRIPTION (provided by applicant): This application is a competitive renewal of the Autoimmunity Center of Excellence (ACE) at Duke. Its research focus will continue to be modulation of B cell responses in autoimmune disease. The ACE will be under the leadership of Dr. E. William St. Clair, Professor of Medicine and Immunology. For the past 5 years, Duke has been a productive member of the ACE network, contributing new insights into the developmental pathways of B cells and the mechanisms of B cell directed therapy. The proposed ACE builds on these discoveries and will support 2 new basic science projects, 5 ongoing and 2 new clinical trials, and an Administrative Core, and continue to emphasize a strong and fluid integration between the bench and the bedside. Tedder and colleagues have recently found that a phenotypically unqiue subset of B cells secreting IL-10 (called B10 cells) serve as critical negative regulators during adaptive CD4+ T cells responses, and dramatically suppress Th1 immune responses and autoimmune disease in mice. For Basic Research Project 1, they will examine the hypothesis that antigen-specific regulatory B10 cells modulate autoimmune responses in mice and man and that they can be manipulated for therapeutic gain. A picture is gradually emerging about the precursors of self-reactive B cells in autoimmune disease. Kelsoe and coworkers in Basic Research Project 2 will investigate developmentally regulated expression of activated cytidine deaminase (AID) in human fetal and neonatal pre-, pro, and immature/transitional B cells and its relationship to the generation of self-reactive B cells in human autoimmune disease, potentially eludidating another pathway of B cell self-reactivity outside the confines of normal tolerance mechanisms. We propose two new clinical trials to investigate lymphotoxin-beta receptor fusion protein as a treatment for primary Sj"gren's syndrome, and rituximab therapy for bullous pemphigoid. A Pilot Research Project is also proposed to engineer tetramers of self-antigen enabling the identification and characterization of self-reactive B cells, which will have implications for the goals of the clinical and other basic research projects. Overall, the Duke ACE will bridge these basic and clinical studies to advance our understanding of autoimmune disease. The B cell is a type of immune cell essential to autoimmunity. The goal of the proposed Autoimmunity Center of Excellence at Duke is to improve our understanding of the roles played by B cells in human autoimmune disease. The projects are designed to be highly integrative between the bench and the bedside, with collaborations between basic and clinical scientists. These studies may lead to better treatments. CLINICAL COMPONENT: Clinical Component (ST CLAIR, W) CLINICAL COMPONENT DESCRIPTION (provided by applicant): The Clinical Research Component of the Autoimmunity Center of Excellence shares with the Basic Research omponent an overall goal of advancing our understanding about the role of B cells in the pathogenesis of autoimmune diseases. This component will be directed by Dr. E. William St. Clair. During the past 5 years, the Duke ACE has brought 3 new clinical trial concepts to the ACE Steering Committee, resulting in 1 completed trial, 1 ongoing trial, and 1 protocol in development. We are also participating in 3 other ongoing ACE-sponsored clinical trials. Therefore, substantial clinical research activity will carry over to the next funding cycle. Our center is organized to support clinical trials in rheumatology, dermatology, gastroenterology, hematology, and neurology. We have access to several large patient populations, including patiens with rheumatoid arthritis, systemic lupus erythematosus, primary Sj"gren's syndrome, scleroderma, autoimmune blistering disease, psoriasis, inflammatory bowel disease, autoimmune hepatitis, anti-phospholipid antibody syndrome, and myasthenia gravis. Each of these disease areas has leadership from one or more physician-investigators with significant clinical trial experience, including an example of a productive inter-institutional collaboration. The physician leadership is supported by an ample infrastructure that provides clinical research space, infusion facilities, experienced clinical coordinators, and an Immune Monitoring Component. The Clinical Research Component aligns with the ACE at a thematic level, with substantial collaborations between basic and clinical scientists. To this end, the proposed clinical trial concepts will focus on B cell directed therapy. In one case, we propose to examine the clinical efficacy of lymphtoxin-beta receptor fusion protein in the treatment of primary Sj"gren's syndrome, and have already secured commitment from the industry sponsor to provide study drug for this trial. The other application will investigate rituximab as initial therapy for bullous pemphigoid. The mechanistic studies for these proposed trials as well as current trials are highly integrated with the basic research projects. The Clinical Research Component will make a significant contribution to the ACE enterprise during the upcoming funding cycle. The Clinical Research Component will support clinical trials sponsored by the Autoimmunity Centers of Excellence in several disease areas, including rheumatology, dermatology, gastroenterology, hematology, and neurology. It has been productive during the current funding cycle, and has the capability, as shown in this application, to generate new ideas for clinical trials that can be translated into well-designed studies.