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）影响了近3000万美国人，因此构成了一个主要的健康问题，并在美国造成了巨大的医疗费用。除了多年生和季节性的AC会降低生活质量外，春季或特应性AC的晚期形式也会对视力造成威胁。不幸的是，目前的药物治疗只是暂时有效，无法消除体征和症状。例如，抗组胺药和肥大细胞稳定剂靶向IgE介导释放的促炎细胞因子和组胺。然而，在此之前，有重要的上游活动不是这些药物的目标，即树突状细胞（DC）刺激T辅助2淋巴细胞。因此，针对DC功能的新策略可能是治疗AC的更好手段。为此，这些拟议研究的总体目标是更好地了解结膜DC和AC免疫发病机制。目前的理解是，DC起源于不同的谱系，这些谱系产生不同的子集，并执行固有或专门的功能，我们实验室最近的工作已经开始对子集和构成conj DC网络的各自本体进行分类。首先，这允许与先前在其他粘膜组织中发现的DC亚群进行比较，例如构成肺或肠道的那些也会发生过敏性炎症。此外，在conj中识别这些DC亚群将有助于本研究的目的1，即辨别哪些DC亚群在AC中具有免疫致病性，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现来实现。关于conj DC介导的T细胞刺激，本提案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，抑制后续T细胞刺激所需的DC成熟。因此，本研究的目的2旨在探索TSP-1缺乏在AC免疫发病机制中的作用。总之，这些研究的结果将进一步了解conj DC亚群和功能，这一领域不仅适用于过敏，也适用于感染性疾病和其他影响眼表的免疫相关疾病。此外，确定AC中的免疫致病性DC亚群及其机制将为开发急需的治疗策略提供重要见解，以更好地治疗AC。

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.