FUNCTIONAL CHARACTERIZATION OF ANERGIC HELPER T CELLS

体内对外周自身抗原的免疫耐受取决于 几种机制的联合作用：克隆无反应性，缺失， 压抑和克隆无知 每种机制都是抗原- 具体;因此，了解其基本性质， 作为设计合理战略的基础， 自身免疫性疾病的治疗。 在该项目下开展的工作 过去的研究集中在免疫应答的调节， 使用克隆的CD 4 + T细胞的克隆无能机制。 我们 实验表明，克隆无反应性不仅抑制T细胞生长， 通过阻断自分泌生长因子的分泌， 阻断淋巴因子反应性的上调。 克隆 无反应性被发现与一种缺陷有关， 到达MAP激酶ERK和JNK，这导致 减少AP-1蛋白c-Fos和JunB的诱导，两者都 对于5' IL-2基因增强子处的反式激活至关重要。 NAFTp， 另一方面，可以在无反应性T细胞中被激活。 一致 由此，除了IL-2以外的淋巴因子（例如，IL-4）可以被诱导 不同程度，CD 40 L表达也是如此，无能T细胞可以 在体外仍刺激B细胞生长和分化。 最后 对这些克隆T细胞的研究使我们了解了 死亡抑制蛋白Bcl-2和Bcl-x。 最近的工作有 建立了T细胞耐受性的体内模型， 克隆无反应性的诱导。 回收的TCR转基因T细胞 来自在没有佐剂的情况下暴露于可溶性抗原的动物 证明不能产生IL-2。 在实验中 在本申请中提出，这些耐受性T细胞将被研究， 用于证明信号转导缺陷， 评估它们参与抗体和细胞介导的 免疫反应。此外， 耐受性T细胞将被检查，这将与它们的 各种死亡抑制物和效应蛋白的表达。最后通过一个 抗原诱导的关节炎模型将测试这种方法的能力， T细胞耐受诱导，以防止发展中国家的 炎症性疾病。 获得的数据将扩大我们的 理解外周自我耐受的调节，如所追求的 在这个项目下，以及作为一个基本的 发展治疗方法，以解决人类 自身免疫性疾病

Immune tolerance to peripheral self-antigens in vivo depends on the combined effects of several mechanisms: clonal anergy, deletion, suppression, and clonal ignorance. Each mechanism is antigen- specific; therefore, an understanding of their underlying nature could serve as a foundation for the design of rational strategies for the treatment of autoimmune diseases. Work under this project in the past has focused on the regulation of immune responsiveness by the clonal anergy mechanism using cloned CD4 plus T cells. Our experiments revealed that clonal anergy inhibits T-cell growth not only by blocking secretion of an autocrine growth factor, but also by blocking the up-regulation of lymphokine responsiveness. Clonal anergy was found to be associated with a defect that prevents signals from reaching the MAP kinases ERK and JNK, and that results in reduced induction of the AP-1 proteins c-Fos and JunB, both of which are critical for transactivation at the 5' IL-2 gene enhancer. NAFTp, on the other hand, could be activated in anergic T cells. Consistent with this, lymphokines other than IL-2 (e.g., IL-4) could be induced to various degrees, as could CD40L expression, and anergic T cells could still stimulate B cells to grow and differentiate in vitro. Finally, the study of these cloned T cells led to an understanding of the regulation of the death-repressor proteins Bcl-2 and Bcl-x. More recent work has established an in vivo model of T-cell tolerance with features indicative of the induction of clonal anergy. TCR transgenic T cells recovered from animals exposed to soluble antigen in the absence of adjuvant demonstrate an inability to produce IL-2. In the experiments proposed in this application, these tolerant T cells will be studied both in vitro and in vivo for evidence of signal transduction defects and to assess their capacity to participate in both antibody- and cell-mediate immune responses. Furthermore, the survival characteristics of the tolerant T cells will be examined, and this will be correlated with their expression of various death-repressor and -effector proteins. Finally, an antigen-induced arthritis model will test the capacity of this method of T-cell tolerance induction to prevent the development of an inflammatory disease. The data obtained will expand our understanding of the regulation of peripheral self-tolerance, as pursued under this program project, as well as serve as a basic for the development of therapeutic approaches to the problem of human autoimmune disease.