CHARACTERIZATION OF THE IMMUNOREGULATORY CIRCUITS IN MAN

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T lymphocytes play a central role in the immune response by specifically recognizing antigens and functioning as effector or regulatory cells. Major recent technical breakthroughs in the molecular characterization of T lymphocyte subsets, and in identification of lymphokines responsible for lymphocyte activation should facilitate the development of important new insights into the immunoregulatory circuits in man. Our long-term objective is directed at defining the structural basis of characterization of the regulatory circuits involved in the generation of both help and suppression in man using a combination of molecular biology, biochemistry and cellular immunology. This information will provide important insights into the nature of molecular and cellular defects seen in autoimmune diseases such as SLE and RA. The specific aims of this proposal are: 1) Activation mechanisms employed by subsets of T4 cells will be studied. Cell surface molecules involved in activation of T4+2H4+ suppressor inducer and T4+4B4+ helper inducer cells will be characterized. Moreover, the spectrum of lymphokines such as IL-2, IL-3, IL-4, IL-5, etc., produced by subsets of T4 cells will be studied. 2) The mechanism by which activated suppressor inducer cells interact with T8 suppressor cells to generate suppressor signals will be studied. The cell surface molecules on activated T4+2H4+ cells or of the recently developed T4+2H4+ suppressor inducer cell line that participate in suppressor cell activation will be studied. We also plan to develop new monoclonal antibodies against the T4+2H4+ suppressor inducer cell line to characterize the antigen recognition unit and to identify new cell surface molecules involved in suppressor inducer function. These antibodies will be used to study the structural basis of suppressor signals in T4+2H4+ suppressor inducer cells. 3) The molecular and cellular basis of defective regulatory circuits in patients with autoimmune diseases will be determined. Differences in the expression of 2H4 and new functional surface molecules, and LCA gene expression in SLE patients will be determined. Mechanisms of generating helper and suppressor signals in SLE patients will also be studied and the specificity of anti-T cell antibodies found in SLE plasma will be determined using transfected target cells. The expression of 4B4 and LCA molecules at both protein and genomic levels in synovial lymphocytes from patients with RA, etc., will also be determined.