REGULATING LYMPHOCYTE PROLIFERATION AND DIFFERENTIATION

淋巴细胞增殖失调可导致自身免疫性 疾病和恶性转化以及免疫缺陷 如X连锁无丙种球蛋白血症。为了有效地干预这种 在这种情况下，有必要靶向控制细胞增殖的分子。 细胞激活级联反应 相反，关键是要了解 临床上用于缓解不必要的药物的机制 淋巴细胞活化，以设计更新更有效的药物 减少副作用。 长期目标是 应用是从分子事件的基本理解开始工作 控制淋巴细胞增殖， 免疫反应。本申请的具体目的是：1） 评估血管活性药物喷替福林（PF）对T 细胞活化和分化; 2）检查调节， 原癌基因c-Rel在活化淋巴细胞中的功能;和 3)来描述前B细胞的分子机制 分化TH1/TH2亚群的作用将通过以下方法进行研究： 测定细胞增殖、细胞因子产生和核因子 T细胞克隆的诱导，及其对发育的影响， 前B细胞分化和胎儿胸腺中的两个模型系统 器官培养转染试验将用于鉴定 在T细胞中差异保留该蛋白的c-Rel结构域 细胞质，并评估c-Rel是否直接激活IL-2 启动子 此外，与促有丝分裂c-Rel相关的蛋白质将 通过免疫沉淀和免疫印迹鉴定。这些研究 将提供关于淋巴细胞功能如何受到影响的见解， 在慢性戊氨酰茶碱治疗期间， 控制淋巴细胞增殖。

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.