The overall goal of this proposal is to explore the ability of monoclonal anti-B2m antibodies to alter lymphocyte function and to define the mechanisms involved. Beta-2-microglobulin (B2m) is the light chain of major histocompatibility (MHC) and major histocompatibility-related cell surface structures. Xeonantibodies against human B2m are capable of altering in vitro lymphocyte function. In general, they augment B cell function but suppress T cell responses. Antibodies to B2m also occur naturally. They are found in several rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, and ankylosing spondylitis. Their clinical significance is unknown, but it is possible they may play a role in pathogenesis. Preliminary studies show that monoclonal anti-B2m can alter lymphocyte and platelet function. In addition, individual monoclonal antibodies against B2m have dramatically different functional effects. Since B2m may combine with several different heavy chains and other molecules have structural similarity to B2m, a variety of possibilities exist for the site of action of anti-B2m antibodies on lymphocytes. Anti-B2m monoclonals should prove useful as probes to define the mechanism of action of anti-B2m antibodies on lymphocytes and clarify the role of B2m containing structures in lymphocyte proliferation. A panel of monoclonal anti-B2m antibodies will be expanded to include individual reagents with optimal ability to alter specific lymphocyte functions such as B cell differentiation or suppression of T cell proliferation. These antibodies will be reacted against cell supernatants containing cytokines or directly with lymphocytes and monocytes to determine whether the effect is due to binding to the cell surface or to soluble mediators. If cells are involved directly, isolated subpopulations of T & B cells will be examined to determine if effector or controlling cells are the site of action. Finally, surface or soluble antigens thought to represent the site of action of the antibodies will be characterized by immunoprecipitation and immunodepletion in conjunction with SDS-PAGE and isolated using the monoclonal as an immunoabsorbant. Proof that the isolated material is relevant will be sought with second generation monoclonals.
