INDIRECT ALLORECOGNITION AND T CELL COSTIMULATION PATHWAYS IN CHRONIC REJECTION

T细胞对同种异体抗原的识别是关键的初始事件 最终导致同种异体排斥反应和移植物丢失。现在很清楚了 同种异体识别有两条不相互排斥的途径。在……里面 “直接”途径T细胞识别供体上完整的异体MHC分子 细胞，而在间接途径中T细胞识别处理 同种异体抗原由反应者(自身)抗原提呈为多肽 细胞(APC)。尽管已经很好地证实了这两条途径 植入后早期活跃，其中任何一条途径的贡献 对同种异体移植排斥反应过程的同种异体识别仍不清楚。 有证据表明，早期急性同种异体移植排斥反应 主要由直接途径介导，因为移植物含有一种 大量供者来源的客运APC(特别是树突状 细胞)，呈现高密度的完整供体MHC分子。 另一方面，慢性排斥反应可能主要是通过 CD4+T细胞识别过程中的间接同种异体识别 同种异体抗原及其对迟发型超敏反应的影响 帮助B细胞产生同种异体抗体。从可用位置 MHC分子特定多态多肽的序列数据可以是 人工合成，这些都为研究血管紧张素转换酶的作用提供了新的途径 慢性排斥反应中的间接同种异体识别。 现在公认的是T细胞需要2个信号才能完全激活。这个 第一个信号是通过T细胞受体(TCR)与 异源抗原由APC以多肽的形式呈现，从而提供 免疫反应的抗原特异性。第二个是“共同-- 刺激“信号，其最好的特征是通过 T细胞辅助分子CD28与B7家族(B7-1)的相互作用 和B7-2)的受体，体外，阻断共刺激 信号抑制T细胞活化并诱导抗原特异性状态 反应迟钝。在体内，阻断CD28-B7共刺激的药物有 事实证明，在抑制免疫反应方面非常有效 急性移植排斥反应的实验模型；联合免疫球蛋白的作用 慢性排斥反应中的刺激性阻断尚未被研究。 我们的假设是T细胞对处理后的同种异体抗原的识别 间接途径是慢性排斥反应的关键和持续特征 导致T细胞的持续招募和激活，以及 CD28-B7共刺激通路是完全激活所必需的 这些启动必要的效应器机制的T细胞 慢性排斥反应的发展。推论的假设是 旨在阻止间接同种异体识别和/或CD28-B7的策略 协同刺激应该阻止发育，甚至中断进展， 慢性同种异体移植排斥反应。我们计划使用已建立的大鼠模型 (F344)在慢性肾移植排斥反应中的作用研究 慢性同种异体移植排斥反应的间接免疫识别 通过阻断这一途径来抑制其发展的手段。

T cell recognition of alloantigens is the key initial event which ultimately results in allograft rejection and graft loss. It is now clear that there are two non-mutually exclusive pathways of allorecognition. In the "direct" pathway T cells recognize intact allo-MHC molecules on donor cells, while in the indirect pathway T cell recognize processed alloantigen presented as peptides by responder (self) antigen-presenting cells (APCs). Although it is fairly well established that both pathways are active early after engraftment, the contribution of either pathway of allorecognition to the process of allograft rejection remains unclear. There is some evidence to suggest that early acute allograft rejection is predominantly mediated by the direct pathway, since the graft contains a significant number of donor-derived passenger APCs (particularly dendritic cells) which present a high density of intact donor MHC molecules. Chronic rejection, on the other hand, may be predominantly mediated by indirect allorecognition where CD4+ T cells recognize processed alloantigens and effect delayed type hypersensitivity (DTH) responses and provide help to B cells for production of alloantibodies. From available sequence data for MHC molecules specific polymorphic peptides can be synthesized, and these provide a novel approach to study the role of indirect allorecognition in chronic rejection. It is now accepted that T cells need 2 signals for full activation. The first signal is provided by engagement of the T cell receptor (TCR) with the foreign antigen presented as a peptide by APCs, and thus provides antigen-specificity to the immune response. The second is a "co- stimulatory" signal, the best characterized of which is provided through the T cell accessory molecule CD28 interacting with the B7 family (B7-1 and B7-2) of receptors on APCs, In vitro, blockade of co-stimulatory signals inhibits T cell activation and induces a state of antigen-specific unresponsiveness. In vivo, agents which block CD28-B7 co-stimulation have proven extremely effective in inhibiting the immune response in experimental models of acute transplant rejection; the role of co- stimulatory blockade in chronic rejection has not been investigated. Our hypothesis is that T cell recognition of processed alloantigen in the indirect pathway is a key and ongoing feature of chronic rejection resulting in the continuous recruitment and activation of T cells, and that the CD28-B7 co-stimulatory pathway is necessary for full activation of these T cells which initiate the necessary effector mechanisms for development of chronic rejection. The corollary hypothesis is that strategies targeted at blocking indirect allorecognition and/or CD28-B7 co-stimulation should prevent development, or even interrupt progression, of chronic allograft rejection. We plan to use an established rat model (F344 into LEW of chronic renal allograft rejection to study this role of indirect aIlorecognition in chronic allograft rejection, and specific means to inhibit its development by interrupting this pathway.