Cellular and Molecular Mechanisms that Contribute to Ocular Surface Allergy

项目摘要 过敏性结膜炎（AC）影响近3000万美国人，从而构成主要的健康问题， 在美国造成了巨大的医疗费用。除了常年性和季节性的AC 这会降低生活质量，晚期的春季或特应性AC也会威胁视力。 不幸的是，目前的药物治疗只是暂时有效，不能消除症状， 症状抗组胺药和肥大细胞稳定剂，例如，靶向IgE介导的释放 促炎细胞因子和组胺。然而，在此之前， 这些药物的靶向作用，即树突状细胞（DC）刺激辅助性T细胞2淋巴细胞。照经上所 很可能，新的策略，针对DC功能，可能作为一个更好的手段来治疗AC。为此中央 这些拟议研究的总体目标是更好地了解结膜（conj）DC及其机制 用于AC免疫发病机制。目前了解到DC起源于不同的谱系 它们产生不同的子集，并执行内在或专门的功能，我们实验室最近的工作 发起了构成conj DC网络的子集和相应个体发育的分类。这一点 其一，允许与先前在其他粘膜组织中鉴定的DC亚群进行比较，例如那些 构成肺或肠，其也维持过敏性炎症。此外，这种DC子集的识别 将有助于本研究的目的1，即辨别哪种DC亚群在AC中是免疫病理性的， 无论这是通过熟练的T细胞刺激和/或增强的过敏原摄取和呈递来实现的。 关于Conj DCs介导的T细胞刺激，本提案中提出的初步研究表明， 血小板反应蛋白（TSP）-1是一种具有免疫调节功能的基质细胞糖蛋白， 成熟所需的后续T细胞刺激。因此，本提案的目标2寻求探讨以下方面的作用： TSP-1缺陷在AC免疫发病机制中的作用总之，这些研究的结果将进一步提供 了解Conj DC亚群和功能，这一领域不仅适用于过敏，而且适用于 感染性疾病和其它影响眼表面的免疫相关病症。此外，识别 AC中免疫病理性DC亚群及其机制的研究将为 开发急需的治疗策略，以更好地治疗AC。

PROJECT SUMMARY Allergic conjunctivitis (AC) affects nearly 30 million Americans, thereby constituting a major health problem and causing significant health care costs in the United States. In addition to perennial and seasonal forms of AC which can diminish quality of life, advanced forms of vernal or atopic AC can be sight-threatening as well. Unfortunately, current pharmacotherapies are only transiently effective and incapable of abolishing signs and symptoms. Antihistamines and mast cells stabilizers, for example, target IgE mediated released proinflammatory cytokines and histamines. However, this is preceded by important upstream activities not targeted by these drugs, namely the stimulation of T helper 2 lymphocytes by dendritic cells (DC). Thus, it is likely that novel strategies targeting DC function, may serve as a better means to treat AC. To this end, the overall goal of these proposed studies is to better understand conjunctival (conj) DCs and the mechanisms employed toward AC immunopathogenesis. It is currently understood that DCs originate from different lineages which yield distinct subsets and perform intrinsic or specialized functions and recent work from our lab has initiated the classification of subsets and respective ontogenies that constitute the conj DC network. This, for one, permits comparisons to DC subsets previously identified in other mucosal tissues, such as those constituting lung or gut, which also sustain allergic inflammation. Furthermore identification of such DC subsets in conj will facilitate Aim 1 of this study, which is to discern which DC subset(s) is immunopathogenic in AC and whether this is accomplished via proficient T cell stimulation and/or enhanced allergen uptake and presentation. Regarding T cell stimulation mediated by conj DCs, preliminary studies presented in this proposal demonstrate that thrombospondin (TSP)-1, a matricellular glycoprotein with immunoregulatory functions, inhibits DC maturation required for consequent T cell stimulation. Thus, Aim 2 of this proposal seeks to explore the role of TSP-1 deficiency in the immunopathogenesis of AC. In summary, results from these studies will provide further understanding of conj DC subsets and function, an area which is not only applicable to allergy but also to infectious diseases and other immune-related conditions afflicting the ocular surface. Furthermore identification of the immunopathogenic DC subset(s) in AC and their mechanisms will provide important insights for development of much needed therapeutic strategies to better treat AC.