Modulation of B Cell Responses in Autoimmunity

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DESCRIPTION (provided by applicant): The proposed Center will focus on the modulation of B cell responses in autoimmunity and will be under the leadership of Dr. E. William St. Clair, Professor of Medicine, Division of Rheumatology. It unites a team of outstanding and experienced basic and clinical investigators. In autoimmunity, B cells not only serve as the source of pathogenic autoantibodies, but they also may function as antigen presenting cells (APCs) and stimulate pathologic inflammation through a variety of mechanisms. B cell function is regulated via the B cell receptor complex as well as other B cell-specific cell surface antigens, including CD20 and CD22. Growing evidence, including our results, indicates CD20 and CD22 are attractive targets for immunotherapy of autoimmune diseases. In addition, we have shown inflammatory stimuli, such as tumor necrosis factor alpha (TNFalpha), can promote the emigration of B cells from the bone marrow, transferring large numbers of developing B lymphocytes to the periphery. We hypothesize aberrantly activated B cells are pivotal to the clinical expression of autoimmunity, and the resulting inflammatory state affords an environment for abnormal development of autoreactive B cells and further dysregulation of the immunological response. Two interrelated basic research projects are proposed to investigate this hypothesis. Dr. Thomas Tedder, Professor and Chair of Immunology, will direct a project examining the roles of CD20 and CD22 in the regulation of B cell function in mouse, taking advantage of a unique panel of CD20 and CD22-directed monoclonal antibodies developed in his laboratory. The other project will be headed by Dr. Garnett Kelsoe, Professor of Immunology, and will investigate to what extent inflammatory stimuli, such as TNFalpha influence the trafficking of immature B cells and selection of the autoreactive B cell repertoire. A clinical component led by Dr. St. Clair and other experienced physician-scientists will complement the basic research projects. This group has expertise in rheumatoid arthritis (RA), systemic lupus erythematosus, pemphigus vulgaris (PV), and other autoimmune diseases as well as access to many different patient populations for clinical studies. One of the proposed trials will evaluate the safety and clinical efficacy of anti-CD22 monoclonal antibody therapy for RA, while the other will investigate infliximab (anti-TNFalpha) therapy for PV. Each of the trials includes mechanistic studies that are integrated with the goals of the basic research projects, providing synergy within the Center. An Administrative Core will oversee the management of these projects. Overall, the Proposed Center will efficiently bridge basic and clinical investigations and should produce new insights into the immunotherapy of autoimmune disease.