Activation, Apathy, Anergy and Apoptosis in Transplantation

描述（由申请人提供）：移植是许多终末期器官疾病的首选治疗方式。移植的成功已经建立在控制T细胞依赖的排斥过程的治疗方法上。目前的治疗方法可以控制排斥反应，但会引起许多非免疫毒性。在过去的几年里，通过靶向T细胞共刺激途径来控制排斥反应的概念在临床试验中显示出了希望。虽然在许多实验性排斥模型中非常有效，但人们普遍认为靶向CD28和/或CD40的共刺激阻断方法并不能均匀地控制排斥反应。随着这些策略在临床试验中的进展，解剖T细胞逃避这些途径封锁的机制变得更加迫切。在过去的几年中，程序化分化模型已经成为理解T细胞反应的新范式。该模型基于证据表明，经过短暂的抗原刺激后，T细胞开始进行几轮细胞分裂和分化为效应细胞的自主克隆扩增。然而，T细胞程序是灵活的，可以被初始启动条件和程序执行过程中的外部因素所改变。两个与移植特别相关的发现是最近的研究，表明1)应答人群的初始前体频率对程序有强大的影响，高初始CD8+ T细胞频率可以将辅助依赖性应答转化为辅助独立型和共刺激独立型应答，2)IL-2和IFN？在CD8+ T细胞不依赖抗原的扩增/分化阶段发挥关键作用。实验证据表明，初始个体的T细胞库中有0.1-10%能够与异体抗原发生反应，这一数字比估计的病毒特异性T细胞反应的前体频率高2-3倍。该建议的中心假设是供体反应性CD4和/或CD8 T细胞初始前体频率的变化是对CD28/CD40共刺激阻断诱导的移植物接受的易感性或抗性的关键决定因素。

DESCRIPTION (provided by applicant): Transplantation is the preferred mode of therapy for many forms of end-stage organ disease. 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 paradigm 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-2 and IFN? 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 CD8 T cells is a critical determinant in the susceptibility or resistance to CD28/CD40 costimulation blockade induced graft acceptance.