Adhesion Molecules in Uveitis

描述（由申请人提供）：自身免疫性后葡萄膜炎是一种炎症性眼病，大多数患者会导致视力丧失。免疫抑制治疗可以减轻炎症，但目前可用的药物非特异性作用，并且具有相当大的毒性。这项工作的总体目标是改善自身免疫性后葡萄膜炎患者的临床结果。实验模型的研究已经确定CD4+ T细胞是炎症的启动者。辅助T细胞亚群从循环中穿过视网膜血管内皮进入眼后段。外渗是由一组特定的内皮粘附分子介导的。人类和老鼠的免疫系统有很大的不同。然而，与对小鼠这一过程的广泛研究相比，很少考虑在人类疾病中起作用的基本机制。该项目基于视网膜内皮细胞上表达的粘附分子在人类后自身免疫性葡萄膜炎的发展中起关键作用的假设，并代表了治疗干预的新靶点。利用原代内皮细胞培养和分析技术，在人视网膜内皮细胞上鉴定了需要进一步研究的粘附分子。这些分子对Th1和Th17细胞在人视网膜内皮上迁移的影响将在粘附和迁移实验中进行研究。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，但表达是细胞特异性和刺激特异性的。ICAM-1在视网膜内皮细胞中的转录调节将通过启动子报告表达和电泳迁移转移试验进行评估。活化白细胞-细胞粘附分子（Activated leukocyte-cell adhesion molecule， ALCAM）是一种从未在视网膜内皮上发现的新型粘附分子。在自身免疫性后葡萄膜炎中的表达和潜在功能将被研究。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Posterior uveitis is an inflammation that occurs within the eye and may result in blindness. Present treatments are not directed specifically at the inflamed tissues, and consequently they cause toxicity. This work, which aims to identify the molecules that allow white blood cells to enter the human eye from the bloodstream at the onset of disease, should suggest new targets for safer drugs to treat patients with posterior uveitis.