CONDITIONED UNRESPONSIVENESS IN ORGAN TRANSPLANTATION

我们建议采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 移植器官的水平。 这是根据最近 证据表明，异常信号转导引起的不适当的 抗原呈递影响核调节因子与 淋巴因子基因的启动子区域以及其他可能导致 淋巴细胞失活和/或重编程，以及 有证据表明，有限数量的T淋巴细胞已经经历了这种 功能开关用于调节免疫细胞内的同种免疫应答， 移植物的微渗漏。 具体目标1定义了 浸润性T细胞表达的确定表位抗原受体 由移植物承担。 具体目标2解决了以下问题的敏感性： 功能和表型可区分的T细胞克隆， 失活/重编程。 特定目标3定义了分子相关物 淋巴细胞在移植排斥反应和条件性排斥反应中的活化 反应迟钝 具体目标4测试的论文， T淋巴细胞的寡克隆群体已经经历了一个 功能开关由抗原驱动以运行替代程序， 有助于产生一种条件反射的状态， 移植物的微环境，允许移植物的长期存活。 器官. 条件性无反应的决定因素分析 在同种异体移植器官的水平上， 调节临床移植中的（同种）免疫应答， 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.