ROLE OF CYTOTOXIC CELLS IN ALLOIMMUNE RESPONSES

细胞介导的细胞毒性已被证明是细胞毒性的主要组成部分。 针对同种异体组织的免疫反应。 亮-亮-OMe 已经观察到人或鼠白细胞的治疗消耗了 自然杀伤细胞、细胞毒性T淋巴细胞（CTL）、CTL前体和 骨髓来源的细胞，而T辅助细胞、B细胞和 非骨髓来源保持功能完整。 此外，Leu- Leu-OMe处理供体细胞可防止致死性肿瘤的发生。 半同种异基因MHC相异鼠移植物抗宿主病 骨髓移植模型。 选择性杀伤 细胞毒性淋巴细胞和髓样细胞， 依赖于高水平二肽基肽酶I的存在 （DPPI）在这些细胞的特化颗粒内。 整体 该项目的目标是利用关于 Leu-Leu-OMe和DPPI的生物化学，以探测生物化学的许多方面。 细胞毒性细胞的生理学，其颗粒的生物学和 这些细胞在移植物抗宿主病和同种异体移植中的作用 排斥反应 具体目标是：（1）评估DPPI产生的作用 膜溶解（Leu-Leu）n-OMe产物诱导DPPI内的细胞凋亡- （2）验证DPPI在细胞增殖中的作用 在小鼠颗粒酶A和B的翻译后加工中;（3）测试 在CTL活化过程中DPPI活性的抑制 损害依赖于颗粒丝氨酸蛋白酶的效应子功能 活性;和（4）描绘DPPI富集细胞和细胞增殖的作用。 DPPI酶活性在体内代谢过程中的作用 同种免疫反应

Cell mediated cytotoxicity has been shown to be a major component of the immune responses directed against allogeneic tissues. Leu-Leu-OMe treatment of human or murine leukocytes has been observed to deplete natural killer cells, cytotoxic T lymphocytes (CTL), CTL precursors and cells of myeloid origin, while T helper cells, B cells and cells of non-bone marrow origin remain functionally intact. Moreover, Leu- Leu-OMe treatment of donor cells prevents development of lethal graft-versus-host disease in a semi-allogeneic MHC disparate murine model of bone marrow transplantation. The selective killing of cytotoxic lymphocytes and myeloid cells by this agent has been shown to be dependent upon the, presence of high levels of dipeptidyl peptidase I (DPPI) within the specialized granules of these cells. The overall goals of this project are to make use of new information on the biochemistry of Leu-Leu-OMe and DPPI to probe a number of aspects of the physiology of cytotoxic cells, the biology of their granules and the role of these cells in graft versus host disease and allograft rejection. The specific aims are: (1) Assess the role of DPPI generated membranolytic (Leu-Leu)n-OMe products in inducing apoptosis within DPPI- enriched cells; (2) Test the proposition the DPPI plays an obligate role in post-translational processing of murine granzymes A and B; (3) test the hypothesis that inhibition of DPPI activity during CTL activation impairs effector functions dependent upon granule serine protease activity; and (4) delineate the role of DPPI enriched cells and the specific role of DPPI enzymatic activity in the evolution of in vivo alloimmune responses.