Cellular and Molecular Mechanisms that Contribute to Ocular Surface Allergy

项目总结 过敏性结膜炎(AC)影响着近3000万美国人，从而构成一个主要的健康问题和 在美国造成了巨大的医疗费用。除了多年生和季节性的AC 这可能会降低生活质量，但高级形式的春季或特应性空调也可能威胁视力。 不幸的是，目前的药物治疗只是暂时有效的，不能消除症状和 症状。抗组胺药物和肥大细胞稳定剂，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，重要的上游活动不是 这些药物的靶向，即树突状细胞(DC)对T辅助2淋巴细胞的刺激。因此，它是 可能针对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(Conj)DC及其机制 用于AC免疫发病机制。目前认为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 开始对构成Conj DC网络的子集和各自的个体发育进行分类。这是为了 其一，允许与以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，也会引起过敏性炎症。此外，识别这样的DC子集 将有助于本研究的目标1，即辨别哪个DC亚群(S)在AC和 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现来实现的。 关于ConJ DC介导的T细胞刺激，本提案中提出的初步研究表明 凝血酶原蛋白(TSP)-1是一种具有免疫调节功能的基质细胞糖蛋白，它抑制DC 随后的T细胞刺激所需的成熟。因此，本提案的目标2试图探讨 TSP-1缺乏在AC免疫发病机制中的作用总而言之，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，也适用于 感染性疾病和其他与免疫有关的疾病折磨着眼表。此外，身份识别 研究AC免疫致病树突状细胞亚群(S)及其机制将为临床治疗提供重要依据。 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.