Identification of human PECAM-1 receptor

描述(由申请人提供)：拟议研究的目标是确定一种人PECAM-1的受体，该受体可能是治疗学家治疗人类移植排斥反应的靶点。这项应用计划使用PECAM-1作为探针来筛选2000多种人类表面蛋白的阵列。该阵列是最近由耶鲁大学医学院的同事、该项目的合作者陈立平博士开发的。它代表了一种非常强大的资源，以前没有人可以用来识别人类受体/反受体。人内皮细胞(EC)作为抗原提呈细胞，影响T细胞的募集，这一事件不仅与移植排斥反应有关，而且可能与涉及免疫成分的一系列人类病理因素有关(例如，自身免疫性疾病和动脉粥样硬化)。有趣的是，只有在正常人外周血中发现的一小部分T细胞，即效应记忆T细胞，在其TCR被EC表面的多克隆TCR刺激试剂激活时，被一种不同的机制招募。这些发现与抗原特异性(或移植物特异性)T细胞在免疫反应中充当先锋的新范式不谋而合。在这个范例中，少量抗原特异性T细胞被招募到感染部位(或移植物)，并通过炎性细胞因子(肿瘤坏死因子和干扰素)调节感染部位，以适应其他免疫细胞的级联。在模拟抗原特异性跨内皮细胞迁移的模型中，EC上的PECAM-1是EM CD4T细胞募集所必需的，但已知的PECAM-1受体均不在EM CD4T细胞上表达。这种受体通过控制抗原(移植物)特异性的EM CD4T细胞的募集，是治疗的潜在有效靶点。这个应用程序建议使用陈博士的新阵列来识别该受体。 公共卫生相关性：同种异体免疫反应是人类移植物失败的主要原因，其特征是移植物血管系统的破坏。我们发现，当人内皮细胞在流动的血液等条件下向T细胞递呈抗原时，通过一种独特的机制诱导T细胞的激活和募集。这些研究将阐明抗原驱动的T细胞募集的分子机制，并可能导致开发特定的治疗方法来改善同种异体移植排斥反应。

DESCRIPTION (provided by applicant): The goal of the proposed research is to identify a receptor for human PECAM-1 that can potentially be targeted by therapeutics to treat human graft rejection. This application proposes to screen an array of more than 2000 human surface proteins using PECAM-1 as a probe. The array was very recently developed by Dr. Lieping Chen, a colleague at Yale University School of Medicine and a collaborator on this project. It represents a very powerful resource not previously available to identify human receptors/counter- receptors. Human endothelial cells (EC) act as antigen presenting cells and affect the recruitment of T cells, an event relevant not only for graft rejection, but potentially or a wide range of human pathologies in which an immune component is implicated (e.g., autoimmune diseases and atherosclerosis). Interestingly, only a small subset of T cells found in the peripheral blood of normal individuals, namely effector memory T cells, are recruited by a distinct mechanism when their TCR is activated by polyclonal TCR- stimulating reagents presented on the surface of the EC. These findings coincide with an emerging paradigm that antigen-specific (or graft-specific) T cells serve as pioneers in an immune reaction. In this paradigm, a small number of antigen-specific T cells are recruited to the site of infection (or a graft) and condition the site via inflammatory cytokines (TNF and IFN-¿) for a cascade of other immune cells. PECAM-1 on the EC is necessary for the recruitment of EM CD4+ T cells in a model mimicking antigen-specific transendothelial migration, yet none of the known receptors for PECAM-1 are expressed on EM CD4+ T cells. This receptor, by controlling antigen (graft) - specific recruitment of EM CD4+ T cells, is a potentially effective target for therapeutics. This application proposes to identify that receptor using Dr. Chen's new array. PUBLIC HEALTH RELEVANCE: Alloimmune reactions are a major cause of human graft failure, characterized by a destruction of the graft vasculature. We have found that human endothelial cells, when presenting antigen to T cells under conditions like that of flowing blood, induce their activation and recruitment by a unique mechanism. These studies will illuminate the molecular mechanisms underlying antigen-driven recruitment of T cells and may lead to the development of specific therapies to ameliorate allograft rejection.