REGULATION OF T LYMPHOCYTE IMMUNE RESPONSES

T 淋巴细胞免疫反应的调节

• 批准号: 3479596
• 负责人: FRANK W. FITCH
• 金额: $ 68.43万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-07-01 至 1994-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3479596
• 关键词: CD2 molecule; CD3 molecule; CD4 molecule; CD8 molecule; MHC class II antigen; T cell receptor; T lymphocyte; antibody dependent killer cell; autocrine; clone cells; cytokine receptors; helper T lymphocyte; histocompatibility; hybrid cells; immune tolerance /unresponsiveness; immunoglobulin idiotypes; immunoregulation; immunosuppression; interleukin 2; laboratory mouse; laboratory rat; leukocyte activation /transformation; leukocyte adhesion molecules; monoclonal antibody; nucleic acid probes

T lymphocytes play an integral role in both cellular and humoral immune responses, carrying out direct effector functions such as cytolysis as well as mediating regulatory functions via secreted lymphokines. The particular functions of T cells are determined by differentiation events that occur independently of the acquisition of the specific receptor for antigen (TCR). The TCR accounts for the specificity of T cell responses. However, several other T cell surface molecules, defined by monoclonal antibodies (mAb), also affect the response of the T cell. These include CD4, CD8, and LFA-1 expressed by human T cells (and the corresponding structures, L3T4, Lyt-2,3, and LFA-1 on murine T cells and CD3 and CD2 (for which murine counterparts have not been identified with certainty). The responses of T cells also are influenced by interleukin 2 (IL-2) which induces T cell proliferation but which also causes cloned murine HTL to become unresponsive to antigen. The proposed studies are concerned with events associated with T cell activation, events associated with development of unresponsiveness of T cells to antigenic stimulation, and development of better approaches to regulate immune responses in vivo. Specifically, we intend to derive mAb reactive with cell surface structures that are important in T cell activation including the murine homologues of human CD3 and the CD2 molecular complex; to determine linkage of T cell surface structures with particular functions by constructing "cytolytic- helper" T cell hybrids using drug-marked cloned murine CTL and HTL as fusion partners; to determine the basis for unresponsiveness induced in cloned murine HTL by exposure to IL- 2 or by exposure to high levels of antigen; to distinguish between cellular events initiated through the TCR (leading to lymphokine production) and those initiated through the IL-2 receptor (leading to proliferation), and to compare the IL-2- dependent and IL-2-independent pathways of proliferation in CTL with the autocrine pathway found in HTL; to determine the properties of "accessory cells" that permit continued replication of cloned murine T cells; to develop additional anti-TCR mAb in order to determine the role of T cell idiotype in immune regulation; to determine the optimal method to achieve immunosuppression in vivo using mAb directed against T cell surface structures; and to determine the functional significance of mAb isotype in allograft enhancement.

T淋巴细胞在细胞和体液免疫中起着不可或缺的作用。 免疫反应，执行直接效应子功能，如 细胞溶解以及通过分泌介导调节功能 淋巴因子 T细胞的特殊功能是由 通过独立于细胞的分化事件， 获得抗原特异性受体（TCR）。 的tcr 解释了T细胞反应的特异性。 但几 其他T细胞表面分子，由单克隆抗体定义 (mAb)也会影响T细胞的反应。 其中包括CD4， 人T细胞表达的CD8和LFA-1（以及 相应的结构，L3T4，Lyt-2，3和LFA-1对小鼠T细胞的作用 细胞和CD3和CD2（对于小鼠对应物， 确定性）。 T细胞的反应也是 受白细胞介素2（IL-2）的影响， 增殖，但也导致克隆的鼠HTL成为 对抗原无反应。 拟议的研究涉及 T细胞活化相关事件， T细胞对抗原的无反应性的发展 刺激和发展更好的方法来管理 体内免疫反应。 具体而言，我们打算获得mAb 与T细胞中重要的细胞表面结构反应， 活化，包括人CD3的鼠同源物和 CD2分子复合物;确定T细胞表面的连接 具有特殊功能的结构，通过构建"细胞溶解- 使用药物标记的克隆鼠CTL的"辅助" T细胞杂交体， HTL作为融合伙伴;确定 在克隆鼠HTL中通过暴露于IL-1诱导的无反应性 2或通过暴露于高水平抗原;以区分 通过TCR启动的细胞事件（导致 淋巴因子产生）和通过IL-2启动的那些 受体（导致增殖），并比较IL-2- CTL增殖的依赖性和非IL-2依赖性途径 与HTL中发现的自分泌途径;以确定 允许持续复制的"辅助细胞"的特性 克隆鼠T细胞;开发额外的抗TCR mAb， 为了确定T细胞独特型在免疫中的作用， 监管;确定最佳的方法来实现 使用针对T细胞的mAb的体内免疫抑制 表面结构;并确定功能意义 同种异体移植物增强的mAb同种型。