REGULATING LYMPHOCYTE PROLIFERATION AND DIFFERENTIATION

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Dysregulation of lymphocyte proliferation can lead to autoimmune diseases and malignant transformation, as well as immunodeficiencies such as x-linked agammaglobulinemia. To effectively intervene in such situations it is necessary to target molecules that control the cellular activation cascade. Conversely, it is critical to understand the mechanisms of drugs that are clinically used to alleviate unwanted lymphocyte activation, in order to design newer more efficient drugs that have decreased side effects. The long term goal of this application is to work from a basic understanding of molecular events that control lymphocyte proliferation to the rational manipulation of immune responses. The Specific Aims of this application are 1) to assess the effects of the vasoactive drug, pentoxifylline (PF), on T cell activation and differentiation; 2) to examine the regulation and function of the proto-oncogene, c-Rel, in activated lymphocytes; and 3) to characterize the molecular mechanisms of pre-B cell differentiation. The effects of TH1/TH2 subsets will be studied by assaying cell proliferation, cytokine production and nuclear factor induction in T cell clones, and its effects on development assayed in two model systems of pre-B cell differentiation and in fetal thymic organ cultures. Transfection assays will be used to identify the domains of c-Rel that differentially retain this protein in the T cell cytoplasm, and to evaluate whether c-Rel directly activates the IL-2 promoter. In addition, proteins associated with mitogenic c-Rel will be identified by immunoprecipitations and immunoblotting. These studies will provide insights into how lymphocyte function may be affected during chronic pentoxifylline treatment and identify targets for controlling lymphocyte proliferation.