Adhesion Molecules in Uveitis

项目摘要 自身免疫性后葡萄膜炎是一种炎症性眼病， 个体免疫抑制治疗可以减轻炎症，但目前可用的药物作用 非特异性的，并且与相当大的毒性有关。这项工作的总体目标是提高 自身免疫性后葡萄膜炎患者的临床结局。实验模型的研究 确定了CD 4 + T细胞作为炎症的启动子。辅助性T细胞亚群从循环中进入 穿过视网膜血管内皮的眼后段。外渗是由一种特异性的 一组内皮粘附分子。人和鼠之间存在显著差异， 免疫系统然而，与对小鼠这一过程的广泛研究相比， 考虑人类疾病的基本机制。这个项目是基于一个假设 视网膜内皮细胞上表达的粘附分子在视网膜血管内皮细胞的发展中起着关键作用， 人后部自身免疫性葡萄膜炎和代表治疗干预新靶点。使用原代 内皮细胞培养和分析技术，粘附分子进一步研究， 在人类视网膜内皮细胞上发现的。这些分子对Th 1和Th 17细胞迁移的影响 将在粘附和迁移测定中研究跨人视网膜内皮的粘附和迁移。细胞间粘附 分子1（ICAM-1）在许多系统中与白细胞外渗密切相关，但表达是细胞- 和刺激特异性。视网膜内皮细胞中ICAM-1转录的调节将使用 启动子报告基因表达和电泳迁移率变动分析。活化白细胞-细胞粘附 ALCAM分子是一种新的粘附分子，以前从未在视网膜内皮细胞上发现过。表达 并将研究与自身免疫性后葡萄膜炎相关的潜在功能。

PROJECT SUMMARY Autoimmune posterior uveitis is an inflammatory eye disease that causes vision loss in a majority of affected individuals. Immunosuppressive treatments may reduce the inflammation, but currently available drugs act non-specifically and are associated with considerable toxicity. The overall objective of this work is to improve the clinical outcomes of patients with autoimmune posterior uveitis. Studies in experimental models have identified CD4+ T cells as initiators of the inflammation. Helper T cell subsets move from the circulation into the posterior segment of the eye across the retinal vascular endothelium. Extravasation is mediated by a specific set of endothelial adhesion molecules. There are significant differences between the human and murine immune systems. Yet, in contrast to the extensive research on this process in the mouse, there has been little consideration of the basic mechanisms operating in human disease. This project is based on the hypothesis that adhesion molecules expressed on retinal endothelial cells participate critically in the development of human posterior autoimmune uveitis and represent novel targets for therapeutic intervention. Using primary endothelial cell cultures and profiling techniques, adhesion molecules warranting further investigation were identified on human retinal endothelial cells. The impact of these molecules on migration of Th1 and Th17 cells across human retinal endothelium will be studied in adhesion and transmigration assays. Intercellular adhesion molecule 1 (ICAM-1) is strongly implicated in leukocyte extravasation in many systems, but expression is cell- and stimulus-specific. Regulation of ICAM-1 transcription in the retinal endothelial cell will be evaluated using promoter reporter expression and electrophoretic mobility shift assays. Activated leukocyte-cell adhesion molecule (ALCAM) is a novel adhesion molecule never before identified on retinal endothelium. Expression and potential functions in relation to autoimmune posterior uveitis will be investigated.