Cellular and Molecular Mechanisms that Contribute to Ocular Surface Allergy

描述（由申请人提供）：过敏性结膜炎（AC）影响近3000万美国人，从而构成了一个主要的健康问题，并在美国造成了巨大的医疗保健费用。除了可降低生活质量的常年性和季节性AC形式之外，春季或特应性AC的晚期形式也可威胁视力。不幸的是，目前的药物治疗只是暂时有效，不能消除体征和症状。例如，抗组胺药和肥大细胞稳定剂靶向IgE介导的释放的促炎细胞因子和组胺。然而，这之前是重要的上游活动，而不是这些药物的目标，即树突状细胞（DC）刺激辅助性T细胞2淋巴细胞。因此，靶向DC功能的新策略可能是治疗AC的更好方法。为此，这些研究的总体目标是更好地了解结膜（conj）DC和AC免疫发病机制。目前理解的是，DC来源于不同的谱系，其产生不同的子集并执行固有或专门的功能，并且我们实验室的最近工作已经启动了构成conj DC网络的子集和相应个体发育的分类。例如，这允许与先前在其他粘膜组织中鉴定的DC亚群进行比较，例如构成肺或肠的那些，其也维持过敏性炎症。此外，这种DC亚群在conj中的鉴定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，以及这是否通过熟练的T细胞刺激和/或增强的过敏原摄取和呈递来实现。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）-1，一种具有免疫调节功能的基质细胞糖蛋白，抑制随后T细胞刺激所需的DC成熟。因此，本提案的目的2旨在探索TSP-1缺陷在AC免疫发病机制中的作用。总之，这些研究的结果将提供对conj DC亚群和功能的进一步理解，这一领域不仅适用于变态反应，而且适用于感染性疾病和其他影响眼表面的免疫相关病症。此外，AC中免疫致病性DC亚群及其机制的鉴定将为开发急需的治疗策略以更好地治疗AC提供重要的见解。 公共卫生相关性：近3000万美国人患有影响眼睛表面的过敏症，从而构成美国的主要健康问题并导致显著的医疗保健成本。不幸的是，目前的药物治疗（如抗组胺药），其目标是导致过敏的终末期生物学事件，不能消除这种情况。这项拟议的研究旨在调查导致过敏的早期事件，从而有助于发现治疗眼部过敏的更有效靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Nearly 30 million Americans suffer from allergies that afflict the surface of the eye, thereby constituting a major health problem in the U.S. and causing significant health care costs. Unfortunately, current drug treatments (such as antihistamines), which target end-stage biological events that cause allergy, do not abolish this condition. The proposed research study seeks to investigate early-stage events that cause allergy and thereby may help to uncover more effective targets for treatment of ocular allergies.