Activation, Apathy, Anergy and Apoptosis in Transplantation

移植是许多终末期器官疾病的首选治疗模式。在以下方面取得成功 移植已经围绕着控制T细胞依赖的过程的治疗方法而建立 拒绝。目前的治疗方法可以控制排斥反应，但会导致许多非免疫性毒性。在过去的几年里 多年来，以T细胞为靶点，通过更多的免疫选择性方法控制排斥反应的概念 共刺激通路在临床试验中显示出了良好的前景。虽然在许多实验中非常有效 排斥模型，人们普遍认为，共刺激阻断方法针对CD28和/或 CD40并不统一控制排斥反应。随着这些策略在临床试验中的进展，有必要 剖析T细胞逃脱这些途径的阻断的机制变得更加紧迫。 在过去的几年里，程序化分化模型已经成为一种新的范式 了解T细胞的反应。这一模型的依据是在短暂的抗原期后 刺激下，T细胞成为致力于自主克隆扩增的几轮程序 细胞分裂和分化为效应细胞。然而，T细胞程序是灵活的，可以通过 初始启动条件和程序执行过程中的外部因素。两项研究发现 与移植特别相关的是最近的研究表明：1)移植的初始前体频率 应答人群对程序和高初始CD8+T细胞有很大影响 频率可以将依赖于助手的反应转换为非依赖于助手的反应和共刺激- 独立反应；2)IL-2和IFNG在非抗原依赖过程中起关键作用。 CD8+T细胞程序扩增/分化阶段。 实验证据表明，一个天真的人的T细胞库中有0.1%-10%能够 与同种异体抗原反应，这个数字比估计的病毒前体频率高2-3个对数- 特异性T细胞反应。这一提议的中心假设是初始前驱体的变化 供者反应性CD4和/或CDS T细胞的频率是易感性或 对CD28/CD40共刺激阻断的抵抗可诱导移植物的接受。

Transplantation is the preferred mode of therapy for many forms of end-stage organ disese. Success in transplantation has been built around therapeutic approaches to control the T cell-dependent process of rejection. Current therapies control rejection but cause numerous non-immune toxicities. In the past few years the concept of controlling rejection with more immuno-selective approaches by targeting T cell costimulatory pathways has shown promise in clinical trials. While very effective in many experimental rejection models, it is widely recognized that costimulation blockade approaches targeting CD28 and/or CD40 do not uniformly control rejection responses. As these strategies progress in clinical trials the need to dissect the mechanisms by which T cells can escape blockade of these pathways becomes more pressing. Over the past several years, the Programmed Differentiation Model has emerged as a new pardigm to understand T cell responses. This model is based on evidence that after a brief period of antigenic stimulation, T cells become committed to a program of autonomous clonal expansion of several rounds of cell division and differentiation into effector cells. However, T cell programs are flexible and can be altered by the initial priming conditions and by extrinsic factors during the execution of the program. Two findings of particular relevance to transplantation are recent studies indicating 1) that the initial precursor frequency of the responding population is a powerful influence on the program and that high initial CD8+ T cell frequencies can convert helper dependent responses into helper-independent and costimulation- independent responses, and 2) that both IL-2and IFNg can play critical roles during the antigen-independent expansion/differentiation phase of the CD8+ T cell program. Experimental evidence suggest that between 0.1-10% of a naive individual's T cell repertoire is capable of reacting with alloantigens, a figure that is 2-3 logs greater than the estimated precursor frequency of virus- specific T cell responses. The central hypothesis of this proposal is that variation in the initial precursor frequencies of donor-reactive CD4 and/or CDS T cells is a critical determinant in the susceptibility or resistance to CD28/CD40 costimulation blockade induced graft acceptance.