Activation, Apathy, Anergy and Apoptosis in Transplantation

在过去4年的资助中，我们定义了T细胞在哪些条件下不需要 在小鼠移植模型中激活和介导移植物排斥反应中的共刺激信号 尽管治疗中使用的试剂会严重抑制T细胞对T细胞的共刺激作用。具体地说，我们的 研究表明，存在较高的幼稚CD4‘^或CDS*T细胞前体频率或前... 供者反应性记忆T细胞的存在使受者难以抵抗 共刺激封锁。这些发现是基于TCR转基因模型的使用，该模型允许 使用固定的、克隆的T细胞群来控制TCR亲和力改变的影响 抗原，以及存在于内源性、多克隆、多抗原特异性群体中的其他变量。 然而，在我们的研究过程中，我们已经开始研究TCR对pMHC的亲和力的作用 移植排斥反应期间的复合体，以及该参数如何从根本上影响移植物排斥反应的大小和 移植排斥或存活期间供者反应性T细胞反应的特征。在建立了一部小说之后 在转基因系统中，移植物特异性T细胞被与TCR亲和力增加的配体启动，我们 已经在初步研究中证明了移植物特异性TCR亲和力深刻地影响了效应器 反应性T细胞的表型，更重要的是，对其易感性有重要影响 共刺激分子阻断诱导移植物存活时间延长。因此，这篇文章中概述的实验 提案将努力阐明TCR亲和力在诱发移植物排斥反应中的作用，并评估 不同效价配体刺激的细胞耐受能力的机制 代价高昂的封锁。这些研究具有重要意义，因为它们将使我们能够开始解开 同种异体反应性T细胞反应的性质，并定义TCR交叉反应的阈值，超过该阈值 会出现T细胞异种交叉反应的临床表现。

In the last 4 years of funding we have defined the conditions under which T cells obviate the requirement for costimulatory signaling during activation, and mediate graft rejection in murine models of transplantation despite treatment with reagents that profoundly Inhibit costimulatory T cells to T cells. Specifically, our research has shown that the presence of high naive CD4'^ or CDS* T cell precursor frequency or pre- existence of donor-reactive memory T cells render recipients refractory to the salutary effects of costimulation blockade. These findings have been based on the use of TCR transgenic models which allow the use of a fixed, monoclonal T cell population in order to control for the effects of altered TCR affinity for antigen, among other variables present In endogenous, polyclonal, polyantigen-specific populations. However, during the course of our studies we have begun to Investigate the role of TCR affinity for pMHC complexes during graft rejection, and how this parameter fundamentally impacts the magnitude and character of the donor-reactive T cell response during graft rejection or survival. After establishing a novel transgenic system In which graft specific T cells are primed by ligands of increasing affinity for the TCR, we have demonstrated In preliminary studies that graft-specific TCR affinity profoundly impacts the effector phenotype of responding T cells, and more Importantly, critically influences their susceptibility to costimulatlon blockade- Induced prolongation in graft survival. Therefore, experiments outlined In this proposal will endeavor to elucidate the role of TCR affinity in precipitating graft rejection, and to assess the mechanisms underlying the ability of cells stimulated with ligands of varying potencies to be tolerized using costlmulatlon blockade. These studies are of great significance because they will allow us to begin to unravel the nature of the alloreactive T cell response, and define a threshold for TCR cross-reactivity above which clinical manifestations of T cell alio- crossreactlvity will occur.