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，导致大多数受影响的个体视力丧失。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，并与相当大的毒性。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局。在实验模型中的研究已经确定了CD 4 + T细胞作为炎症的引发剂。辅助T细胞亚群从循环穿过视网膜血管内皮进入眼后段。外渗由一组特定的内皮粘附分子介导。人和鼠的免疫系统之间存在显著差异。然而，与在小鼠中对这一过程的广泛研究相反，很少考虑在人类疾病中起作用的基本机制。该项目是基于这样的假设，即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，并代表了治疗干预的新靶点。利用原代内皮细胞培养和谱分析技术，在人视网膜内皮细胞上鉴定出了有待进一步研究的粘附分子。将在粘附和迁移测定中研究这些分子对Th 1和Th 17细胞穿过人视网膜内皮的迁移的影响。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。将使用启动子报告基因表达和电泳迁移率变动分析评价视网膜内皮细胞中ICAM-1转录的调节。活化的白细胞-细胞粘附分子（ALCAM）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。将研究与自身免疫性后葡萄膜炎相关的表达和潜在功能。 公共卫生相关性：后葡萄膜炎是一种发生在眼睛内的炎症，可能导致失明。目前的治疗方法并不是专门针对发炎的组织，因此它们会引起毒性。这项工作的目的是确定在疾病发作时允许白色血细胞从血流进入人眼的分子，应该为治疗后葡萄膜炎患者的更安全药物提供新的靶点。

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.