ROLE OF CYTOTOXIC CELLS IN ALLOIMMUNE RESPONSES

同种异体抗原差异诱导的免疫应答包括 诱导同种异体反应性T细胞分泌淋巴因子， 抗原特异性细胞毒性T细胞的活化。 在体外 在同种异体反应的体内模型中， CD 4/L3 T4（+）T细胞产生淋巴因子，增殖， 产生同种特异性细胞毒性T细胞（CTL）， II类主要组织相容性（MHC）抗原， 对I类MHC差异的反应类似地由 CD 8/Lyt 2（+）T细胞。 因为很难把 这两种T细胞内的细胞毒性效应细胞的辅助细胞 很难清楚地划分出具体的 T细胞的功能活动，这是必不可少的进化 同种异体抗原诱导现象的各种体内方面。 一 申请人实验室的一系列研究已经描述了 L-亮氨酰-L-亮氨酸甲酯（Leu- Leu-OMe）对人和鼠细胞毒性细胞的作用。 具体地说， 在与该试剂短暂孵育后，NK细胞和 杀伤CD 4/L3 T4（+）和CD 8/Lyt 2（+）CTL或前CTL 而辅助性T细胞、B细胞或鼠骨髓干细胞 保持活力和功能完整。 此外，在小鼠中， 通过完全MHC屏障的骨髓移植模型， 用该试剂处理供体细胞已经显示出， 防止致命的GVHD的发展。 拟议的研究将 研究细胞毒性细胞在移植物演变中的作用 抗宿主疾病和机制， 通过Leu-Leu-OMe处理这些细胞调节了 同种异体抗原诱导的免疫反应在这种综合征或 同种异体移植排斥模型。 细胞毒性细胞的作用 同种异体免疫耐受的诱导 将被审查。 此外，体内给药方案 将开发Leu-Leu-OMe，并使用这种方法 检查该药剂调节GVHD的能力，或 移植物排斥反应在不同的时间点，在发展过程中， 这些免疫反应。 预计新的见解， 细胞毒性细胞在同种免疫介导中的作用 将获得答复，并提供有关新的 预防人类GVHD或同种异体移植排斥反应的策略。

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.