CYTOTOXIC CELLS AND ALLOIMMUNE RESPONSES

细胞介导的细胞毒性已被证明是 针对同种异体组织的免疫反应。亮-亮-美 已经观察到对人类或小鼠白细胞的治疗会耗尽 自然杀伤细胞、细胞毒性T淋巴细胞(CTL)、CTL前体和 髓系来源的细胞，而T辅助细胞，B细胞和 非骨髓来源的细胞在功能上保持不变。此外，Leu- 供体细胞的Leu-ome治疗可防止致死性疾病的发生 半异基因MHC完全不同小鼠的移植物抗宿主病 骨髓移植模型。有选择地杀害 这种药物对细胞毒性淋巴细胞和髓系细胞的作用已被证明 依赖于高水平的二肽基肽酶I的存在 (DPPI)在这些细胞的特化颗粒内。整体而言 这个项目的目标是利用关于 Leu-Leu-ome和DPPI的生物化学研究 细胞毒细胞的生理学，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物中的作用 拒绝。具体目标是：(1)评估DPPI产生的作用 膜裂解(Leu-Leu)N-OMe产物诱导DPPI- 富含细胞；(2)检验DPPI发挥预定作用的命题 在小鼠颗粒酶A和B的翻译后加工中；(3)测试 CTL激活过程中抑制DPPI活性的假说 依赖颗粒丝氨酸蛋白酶的效应器功能受损 活性；以及(4)描述富含DPPI的细胞的作用和 DPPI酶活性在体内进化中的特殊作用 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.