Activation, Apathy, Anergy and Apoptosis in Transplantation

移植是许多终末期器官疾病的首选治疗方式。成功 移植已经围绕治疗方法建立，以控制T细胞依赖性过程， 排斥反应目前的治疗控制排斥反应，但引起许多非免疫毒性。过去几 多年来，通过靶向T细胞的免疫选择性方法来控制排斥反应的概念 共刺激途径在临床试验中显示出前景。虽然在许多实验中非常有效， 在排斥模型中，广泛认为靶向CD 28和/或CD 29的共刺激阻断方法是有效的。 CD 40并不均匀地控制排斥反应。随着这些策略在临床试验中的进展， 剖析T细胞逃避这些通路阻断的机制变得更加紧迫。 在过去的几年里，程序化差异化模型已经成为一种新的范式， 了解T细胞反应。这个模型是基于这样的证据，即经过短暂的抗原性 刺激后，T细胞开始致力于几轮自主克隆扩增的程序， 细胞分裂和分化为效应细胞。然而，T细胞程序是灵活的，可以通过以下方式改变 初始启动条件和程序执行期间的外部因素。两个发现 与移植特别相关的是最近的研究表明：1） 应答群体对程序有强大影响，高初始CD 8 + T细胞 频率可以将依赖于辅助者的反应转换为不依赖于辅助者的共刺激。 2）IL-2和IFNg在抗原非依赖性免疫应答中均起重要作用， 在CD 8 + T细胞程序的扩增/分化阶段。 实验证据表明，初始个体的T细胞库中的0.1-10%能够与免疫原性结合。 与同种异体抗原反应，这一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。这一建议的核心假设是， 供体反应性CD 4和/或CD 8 T细胞的频率是易感性的关键决定因素， 对CD 28/CD 40共刺激阻断的抗性诱导移植物接受。

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.