Adhesion Molecules in Uveitis

项目总结 自身免疫性后葡萄膜炎是一种炎症性眼病，可导致大多数患者失明。 个人。免疫抑制治疗可能会减轻炎症，但目前可用的药物起作用 非特异性的，并与相当大的毒性有关。这项工作的总体目标是改进 自身免疫性后葡萄膜炎的临床转归。对实验模型的研究已经 确定CD4+T细胞是炎症的起始者。辅助性T细胞亚群从循环进入 眼后段穿过视网膜血管内皮细胞。外渗是由一种特定的 一组内皮细胞黏附分子。人类和小鼠之间存在着显著的差异 免疫系统。然而，与对小鼠这一过程的广泛研究相比，几乎没有什么研究 对人类疾病的基本作用机制的思考。这个项目是基于这样的假设 视网膜内皮细胞上表达的黏附分子在糖尿病视网膜病变的发生发展中起重要作用。 人类后部自身免疫性葡萄膜炎，是治疗干预的新靶点。使用主服务器 内皮细胞培养和图谱技术，值得进一步研究的黏附分子 在人视网膜内皮细胞上鉴定。这些分子对Th1和Th17细胞迁移的影响 将在黏附和迁移试验中研究跨人视网膜内皮细胞。细胞间黏附 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- 以及特定于刺激的。视网膜内皮细胞中ICAM-1转录的调节将使用 启动子报告表达和电泳迁移率改变分析。激活的白细胞-细胞黏附 分子(Alcam)是一种在视网膜内皮细胞上从未发现的新的黏附分子。表达式 并将研究与自身免疫性后葡萄膜炎有关的潜在功能。

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.