MURINE T LYMPHOCYTE SUBSETS AND ALLOGRAFT REJECTION

鼠 T 淋巴细胞亚群和同种异体移植排斥

• 批准号: 3747092
• 负责人: FRANK W FITCH
• 金额: --
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3747092
• 关键词: CD4 molecule; CD8 molecule; MHC class I antigen; MHC class II antigen; T cell receptor; athymic mouse; autologous transplantation; cell type; clone cells; cytotoxic T lymphocyte; flow cytometry; hamsters; helper T lymphocyte; histocompatibility; homologous transplantation; immunoregulation; immunosuppression; immunotherapy; interferons; interleukin 1; interleukin 2; interleukin 4; laboratory mouse; laboratory rat; leukocyte activation /transformation; lymphokines; monoclonal antibody; suppressor T lymphocyte; surface antigens; tissue /cell culture; transplant rejection

T lymphocytes play a central role in cellular and humoral immune responses, and they are responsible for rejection of allografts. Expression of some T cell surface structures correlates with the class of MHC antigen which restricts their responses: generally, CD8 is found on T cells which are restricted by or reactive with class I MHC antigens while CD4 is found on T which are restricted by or reactive with class II MHC antigens. T cells which express CD4 have been subdivided further on the basis of the array of secreted lymphokines: T(H)1 cells secrete IL-2 and IFN-gamma but not IL-4 or IL-5 while T(H)2 cells secrete IL-4 and IL-5 but not IL-2 or IFN-gamma. However, some CD4+ cells do not fit into these categories. While most CD8+ T cells are dependent on growth factors supplied by CD4+ cells, some are helper-independent. Although T cells carry out direct effector functions such as cytolysis and mediate regulatory functions via secreted lymphokines, the mechanisms by which they cause allograft rejection are poorly characterized. Congenic mouse strains which differ in selected regions of the MHC complex provide useful model systems for studying the functions of the different T cell subsets in allograft rejection. Both CD4+ and CD8+ cells appear to be involved in the rejection of murine allografts which differ only in H-2K(b) and I-A(b), while only CD8+ cells appear to be required for rejection of H-2L(d) allografts. The proposed studies will define the kinds of T cells involved in rejection of allografts which differ from the host in specific, defined regions of the MHC complex and with characterizing the mechanisms by which these T cells cause graft rejection. We will: 1) derive cloned T cells reactive with H-2L(d) class I MHC antigen and determine the array of lymphokines produced and the bell surface molecules expressed; 2) characterize the basis for the variable expression of cytolytic activity in some CD8+ CTL which react with H-2L(d) class I MHC antigens; 3) determine whether there are subsets of CD8+ murine T cells corresponding to the T(H)1 and T(h)2 and other subsets of CD4+ murine T cells; and 4) develop strategies for suppressing allograft rejection including use of monoclonal antibodies reactive with lymphokines or cell surface structures on the particular T cells subsets.

T 淋巴细胞在细胞和体液免疫反应中发挥核心作用， 他们负责同种异体移植物的排斥。一些T的表达 细胞表面结构与 MHC 抗原类别相关 限制它们的反应：通常，CD8 存在于 T 细胞上，这些 T 细胞 受 I 类 MHC 抗原限制或与其反应，而 CD4 存在于 T 上 受 II 类 MHC 抗原限制或与其发生反应。 T细胞 表达 CD4 的基因已根据以下数组进一步细分： 分泌性淋巴因子：T(H)1 细胞分泌 IL-2 和 IFN-gamma，但不分泌 IL-4 或 IL-5，而 T(H)2 细胞分泌 IL-4 和 IL-5，但不分泌 IL-2 或 IFN-γ。 然而，一些 CD4+ 细胞不属于这些类别。虽然大多数 CD8+ T 细胞依赖于 CD4+ 细胞提供的生长因子，有些是 独立于助手。尽管 T 细胞执行直接效应功能 例如细胞溶解和通过分泌介导调节功能 淋巴因子，它们引起同种异体移植排斥的机制是 特征不佳。同类系小鼠品系的选择不同 MHC 复合体的区域为研究 不同T细胞亚群在同种异体移植排斥反应中的功能。均为CD4+ CD8+细胞似乎参与了小鼠同种异体移植物的排斥反应 仅 H-2K(b) 和 I-A(b) 不同，而只有 CD8+ 细胞似乎是 排斥 H-2L(d) 同种异体移植物所需的。拟议的研究将 定义参与同种异体移植物排斥反应的 T 细胞类型 MHC 复合体的特定区域与宿主不同，并且 描述了这些 T 细胞引起移植的机制 拒绝。我们将：1) 获得与 H-2L(d) I 类反应的克隆 T 细胞 MHC 抗原并确定产生的淋巴因子阵列和铃声 表达的表面分子； 2）表征变量的基础 一些与 H-2L 反应的 CD8+ CTL 中表达细胞溶解活性(d) I类MHC抗原； 3) 确定是否存在CD8+小鼠亚群 对应于 T(H)1 和 T(h)2 以及 CD4+ 的其他亚群的 T 细胞 小鼠 T 细胞； 4) 制定抑制同种异体移植的策略 排斥反应，包括使用与淋巴因子反应的单克隆抗体 或特定 T 细胞亚群上的细胞表面结构。