APOPTOSIS IN TRANSPLANTATION

描述(摘自申请者的摘要)：细胞凋亡是一种高度 细胞死亡的调节程序。最近的研究表明，细胞凋亡是一种 同种异体排斥反应中组织损伤的重要机制。假设是为了 被测试的是，细胞凋亡在同种异体移植物中具有双重作用，是有害的 作用是移植物细胞损伤的一种机制，而有益的作用涉及 消除同种异体反应细胞。这个项目的总体目标是 在器官移植过程中调节细胞凋亡以抑制移植物死亡 相关细胞和促进删除浸润性宿主反应细胞。 利用明确定义的动物模型进行的一系列综合研究 原位肝移植和小肠移植分别是 建议。在特定的目标1中，移植物凋亡的机制 将对同种异体移植排斥反应期间的损害进行定义。核糖核酸酶保护分析，以及 竞争性逆转录聚合酶链式反应将用于 确定细胞和可溶性启动子以及信号通路 最终导致不可逆转的细胞损伤和死亡。进一步的研究将 利用功能分析法检测caspase的蛋白水解性裂解 在移植排斥反应期间。半胱氨酸天冬氨酸酶激活的特异性多肽抑制剂 应用于同种异体移植受者以阻断细胞凋亡途径和 移植物受损。研究人员此前已经确定CD8+细胞是 对同种异体移植排斥或移植物细胞凋亡不是必需的。细胞凋亡者 因此，独立于CD8细胞发挥作用的途径将被阐明 并在特定目标2中进行调节。在特定目标3中，他们将检查 凋亡在诱导同种异体移植耐受中的作用。最近，他们确定了 大多数宿主CD4+T细胞的耗尽会导致大量的 对移植物损伤最小的移植物浸润性细胞的凋亡 拒绝。侵袭的细胞和生化机制 删除的淋巴细胞将使用此模型进行检查。此外， 传统免疫抑制剂的影响和同种异体反应宿主的缺失 将对淋巴细胞进行研究。细胞凋亡的定义和特征 器官移植的途径将导致新的治疗方法来增强 移植物存活和消除同种异体反应细胞，同时保存宿主 免疫反应。

DESCRIPTION (adapted from applicant's abstract): Apoptosis is a highly regulated program of cell death. Recent studies suggest that apoptosis is an important mechanism of tissue injury in allograft rejection. The hypothesis to be tested is that apoptosis has a dual role in the allograft, a deleterious role is a mechanism of graft cell damage and a beneficial role involving elimination of alloreactive cells. The overall goal of this project is to modulate apoptosis during organ transplantation so as to inhibit death of graft associated cells and to promote deletion of infiltrating host reactive cells. An integrated series of studies utilizing well defined animal models of orthotopic liver transplantation and small intestinal transplantation are proposed. In Specific Aim 1 the mechanisms responsible for apoptotic graft damage during allograft rejection will be defined. RNase protection assays, and competitive reverse transcriptase polymerase chain reaction will be utilized to determine the cellular and soluble initiators as well as the signaling pathways which culminate in irreversible cell damage and death. Further studies will utilize functional assays to examine the proteolytic cleavage of caspases during graft rejection. Specific peptide inhibitors of caspase activation will be administered to allograft recipients to disrupt the apoptotic pathway and graft damage. The investigators have previously determined that CD8+ cells are not essential for allograft rejection or graft cell apoptosis. The apoptotic pathways that function independent of CD8 cells will therefore be elucidated and modulated in Specific Aim 2. In Specific Aim 3 they will examine the role of apoptosis in inducing allograft tolerance. Recently, they have determined that depletion of the majority of host CD4+ T cells results in abundant apoptosis of graft infiltrating cells with minimal allograft damage and rejection. The cellular and biochemical mechanisms by which infiltrating lymphocytes are deleted will be examined using this model. Furthermore, the impact of conventional immunosuppressives and the deletion of alloreactive host lymphocytes will be studied. Definition and characterization of apoptotic pathways in organ transplantation will lead to novel therapeutics to enhance graft survival and eliminate alloreactive cells while preserving the host immune response.