INDIRECT ALLORECOGNITION AND T CELL COSTIMULATION PATHWAYS IN CHRONIC REJECTION

慢性排斥反应中的间接同种异体识别和 T 细胞共刺激途径

• 批准号: 6235536
• 负责人: CHARLES B CARPENTER
• 金额: $ 17.74万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 1998-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6235536
• 关键词: CD antigens; CD28 molecule; MHC class II antigen; T cell receptor; T lymphocyte; clone cells; cytokine; fibrosis; immune tolerance /unresponsiveness; immunocytochemistry; kidney transplantation; laboratory rat; leukocyte activation /transformation; pathologic process; polymerase chain reaction; proteinuria; tissue /cell culture; transplant rejection

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.

T细胞对同种异体抗原的识别是关键的初始事件， 最终导致同种异体移植物排斥和移植物损失。 现在很清楚 有两种非相互排斥的同种异体识别途径。在 “直接”途径T细胞识别供体上完整allo-MHC分子 细胞，而在间接途径中，T细胞识别加工 通过应答者（自身）抗原呈递以肽形式呈递的同种异体抗原 细胞（APC）。尽管这两种途径都被公认为 在移植后早期是活跃的， 同种异体移植排斥反应过程的同种异体识别仍不清楚。 有一些证据表明，早期急性同种异体排斥反应， 主要由直接途径介导，因为移植物含有 大量来源于供体的乘客APC（特别是树突状细胞 细胞），其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由 间接同种异体识别，其中CD 4 + T细胞识别经过处理的 同种异体抗原和影响迟发型超敏反应（DTH）， 为B细胞产生同种抗体提供帮助。从可用 可以获得MHC分子特异性多态性肽的序列数据 合成，这些提供了一种新的方法来研究的作用， 慢性排斥反应中间接同种异体识别 现在公认的是，T细胞需要2个信号才能完全激活。的 第一信号通过T细胞受体（TCR）与 所述外源抗原作为肽被APC呈递，从而提供 免疫反应的抗原特异性。第二个是“合作”。 刺激性”信号，其最佳特征是通过 与B7家族（B7-1）相互作用的T细胞辅助分子CD 28 和B7-2）的受体，在体外，阻断共刺激 信号抑制T细胞活化，并诱导抗原特异性的状态， 反应迟钝在体内，阻断CD 28-B7共刺激的试剂具有 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;共- 尚未研究慢性排斥中的刺激阻断。 我们的假设是，T细胞对同种异体抗原的识别是通过免疫反应来实现的。 间接途径是慢性排斥反应一个关键和持续的特征 导致T细胞的持续募集和活化，以及 CD 28-B7共刺激途径对于完全激活是必要的 这些T细胞启动必要的效应机制， 慢性排斥反应的发展。推论假设是， 靶向阻断间接同种异体识别和/或CD 28-B7的策略 共刺激应该阻止发育，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探讨LEW在肾移植慢性排斥反应中的作用， 慢性同种异体移植排斥反应中间接同种异体识别， 是指通过阻断这一途径来抑制其发展。