APOPTOSIS IN TRANSPLANTATION

描述（改编自申请人的摘要）：细胞凋亡是一种高度 细胞死亡的调控程序。最近的研究表明，细胞凋亡是一种 移植排斥反应中组织损伤重要机制。假设， 细胞凋亡在同种异体移植物中具有双重作用， 作用是移植细胞损伤的一种机制， 消除同种异体反应性细胞。该项目的总体目标是 调节器官移植过程中细胞凋亡，抑制移植物死亡 相关细胞并促进浸润性宿主反应性细胞的缺失。 一个综合的系列研究，利用明确的动物模型， 原位肝移植和小肠移植是 提出了在特定目标1中，负责凋亡移植物的机制 将定义同种异体移植排斥期间的损伤。RNA酶保护测定，和 竞争性逆转录酶聚合酶链反应将用于 确定细胞和可溶性引发剂以及信号通路 最终导致不可逆的细胞损伤和死亡。进一步的研究将 利用功能测定来检查半胱天冬酶的蛋白水解切割 在移植排斥反应期间。胱天蛋白酶激活的特异性肽抑制剂将 给予同种异体移植物接受者以破坏细胞凋亡途径， 移植物损伤研究人员先前已经确定，CD8+细胞是 对同种异体移植物排斥或移植物细胞凋亡不是必需的。凋亡 因此，将阐明独立于CD8细胞发挥功能的途径 并在特定目标2中进行了调整。在具体目标3中，他们将研究 细胞凋亡在诱导同种异体移植耐受中的作用。最近，他们确定 大多数宿主CD4 + T细胞的耗竭导致大量的 移植物浸润细胞凋亡，同种异体移植物损伤最小， 排斥反应细胞和生物化学机制， 将使用该模型来检查淋巴细胞被删除。而且 常规免疫抑制剂的影响和同种异体反应性宿主的缺失 将研究淋巴细胞。凋亡的定义和表征 器官移植的途径将导致新的治疗方法，以提高 移植物存活和消除同种异体反应性细胞，同时保留宿主 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.