ROLE OF CYTOTOXIC CELLS IN ALLOIMMUNE RESPONSES

同种异体抗原差异引起的免疫反应包括 诱导同种异体反应性T细胞分泌淋巴因子 抗原特异性细胞毒T细胞的激活。在这两种体外实验中 在体内的同种异体反应模型中，已经证明 CD4/L3T4()T细胞产生淋巴因子，增殖和 产生同种异体特异性细胞毒性T细胞(CTL)以应对 第二类主要组织相容性(MHC)抗原 对第I类MHC差异的反应也同样由 CD8/Lyt2()T细胞。因为很难分离 这两个T细胞内的辅助细胞来自细胞毒效应细胞 子集，已经很难清楚地描绘出具体的 T细胞的功能活动是人类进化所必需的 体内同种异体抗原诱导现象的多个方面。一个 申请人实验室的一系列调查描述了 L-亮氨酰-L-亮氨酸甲酯的选择性作用 Leu-ome)对人和小鼠细胞毒细胞的影响。具体来说， 在与该试剂短暂孵育后，NK细胞和两者 CD4/L3T4()和CD8/Lyt2()CTL或前CTL被杀死 而辅助性T细胞、B细胞或小鼠骨髓干细胞 保持活力和功能完好无损。此外，在一只小鼠身上 跨越全部MHC屏障的骨髓移植模型， 用这种试剂治疗供体细胞已被证明 防止发生致命性移植物抗宿主病。拟议的研究将 检测细胞毒细胞在移植物进化中的作用 对抗寄主疾病和最初消除疾病的机制 经Leu-Leu-ome处理的此类细胞可调节 同种异体抗原诱导的免疫反应在此综合征或在 同种异体移植排斥反应模型。细胞毒细胞的作用 同种异体免疫耐受诱导机制的研究进展 将会被检查。此外，体内给药的方案 将开发Leu-Leu-ome，并将使用这种方法 检查该制剂调节GVHD的能力或 同种异体移植排斥反应在不同时间点的演变 这些免疫反应。预计对此的新见解 细胞毒细胞在同种异体免疫调节中的作用 将获得答复，并提供有关新的 预防人类移植物抗宿主病或同种异体排斥反应的策略。

Immune responses induced by alloantigenic differences include induction of lymphokine secretion from alloreactive T cells and activation of antigen specific cytotoxic T cells. In both in vitro and in vivo models of alloresponsiveness, it has been demonstrated that CD4/L3T4 (+) T cells produce lymphokines, proliferate and give rise to allospecific cytotoxic T cells (CTL) in response to class II major histocompatibility (MHC) antigens whereas responses to class I MHC differences are similarly mediated by CD8/Lyt2 (+) T cells. Because of the difficulty in separating helper cells from cytotoxic effector cells within these two T cell subsets, it has been difficult to delineate clearly the specific functional activities of T cells which are essential for evolution of various in vivo aspects of alloantigen-induced phenomena. A series of investigations in the applicant's laboratory has described the selective effects of L-leucyl-L-leucine methyl ester (Leu- Leu-OMe) on human and murine cytotoxic cells. Specifically, after brief incubation with this agent, NK cells and both CD4/L3T4 (+) and CD8/Lyt2 (+) CTL or pre-CTL are killed whereas helper T cells, B cells, or murine bone marrow stem cells remain viable and functionally intact. Furthermore, in a murine model of bone marrow transplantation across full MHC barriers, treatment of donor cells with this agent has been shown to prevent development of lethal GVHD. The proposed studies will examine the role of cytotoxic cells in the evolution of graft versus host disease and the mechanism whereby initial elimination of such cells by Leu-Leu-OMe treatment modulates the course of alloantigen-induced immune responses in this syndrome or in models of allograft rejection. The effect of cytotoxic cell delineation on the induction of allospecific immunologic tolerance will be examined. In addition, protocols for in vivo administration of Leu-Leu-OMe will be developed and this approach will be used to examine the ability of this agent to modulate GVHD or allograft rejection at various time points during the evolution of these immune responses. It is anticipated that new insights into the role of cytotoxic cells in the mediation of alloimmune responses will be obtained and information provided regarding new strategies for preventing GVHD or allograft rejection in man.