CONDITIONED UNRESPONSIVENESS IN ORGAN TRANSPLANTATION

我们建议使用分子方法来开发有效的 诱导特异性免疫无反应性的策略 同种异体器官移植水平。这是基于最近的 证据表明异常的信号转导是由不适当的 抗原提呈影响核调节因子与 淋巴因子基因的启动子区域以及可能引起的其他因素 淋巴细胞失活和/或重新编程，以及不断增长的 有证据表明，经历过这种情况的有限数量的T淋巴细胞 一种功能开关用于调节体内的同种免疫反应 移植物的微环境。特定目标1定义了 渗透T细胞表达特定表位的抗原受体 由移植物承担。具体目标2解决的是 功能和表型可区分的T细胞克隆 停用/重新编程。特定目标3定义了分子关联 移植排斥状态和条件化状态下淋巴细胞的激活 反应迟钝。《特定目标4》测试了一个 T淋巴细胞亚群的寡克隆性 功能开关由抗原驱动以运行替代程序，并 用于生成一种有条件的无响应状态 移植物的微环境，使移植物长期存活 管风琴。条件性无反应的决定因素分析 在器官移植的水平上可能会允许新的策略 在临床移植中调节(同种)免疫反应和 待开发的自身免疫性疾病。

We propose to employ a molecular approach to develop effective strategies for inducing specific immunologic unresponsiveness at the level of a transplanted organ allograft. This is based on recent evidence that aberrant signal transduction arising from inappropriate antigen presentation affects binding of nuclear regulatory factors to promoter regions of lymphokine genes and probably others to cause lymphocyte inactivation &/or reprogramming, and a growing body of evidence that limiting numbers T lymphocytes which have undergone such a functional switch serve to modulate alloimmune responses within the microenvironnent of a graft. Specific Aim 1 defines heterogeneity of antigen receptors expressed by infiltrating T cells for defined epitopes borne by the graft. Specific Aim 2 addresses the susceptibility of functional and phenotypically distinguishable T cell clones to inactivation/reprogramming. Specific Aim 3 defines molecular correlates of lymphocytes activation in states of graft rejection and conditioned unresponsiveness. Specific Aim 4 tests the thesis that of an oligoclonal population of T lymphocytes which have undergone a functional switch are driven by antigen to run an alternate program and serve to generate a state of conditioned unresponsiveness within the microenvironment of the graft which permits long term survival of the organ. An analysis of the determinants of conditioned unresponsiveness at the level of the organ allograft may permit new strategies for modulating the (allo)immune response in clinical transplantation and autoimmune disease to be developed.