Cellular and Molecular Mechanisms that Contribute to Ocular Surface Allergy

导致眼表面过敏的细胞和分子机制

• 批准号: 9037256
• 负责人: Daniel Raphael Saban
• 金额: $ 8.01万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9037256
• 关键词: Affect; Allergens; Allergic; Allergic Conjunctivitis; Allergic inflammation; Allergic rhinitis; American; Antihistamines; Area; Biological; Cell Maturation; Cell physiology; Cellular biology; Classification; Communicable Diseases; Conjunctivitis; Contact Lenses; Dendritic Cells; Development; Drug Targeting; Event; Experimental Models; Eye; Giant Papillary Conjunctivitis; Glycoproteins; Goals; Health; Health Care Costs; Histamine; Hypersensitivity; ITGAM gene; ITGAX gene; IgE; Immune; Immune response; Immunity; In Vitro; Inbred BALB C Mice; Investigation; Lung; Lymphocyte; Mast Cell Stabilizer; Measures; Mediating; Molecular; Mucous Membrane; Mus; Nose; Pathogenesis; Pharmaceutical Preparations; Pharmacotherapy; Play; Proteins; Quality of life; Role; Route; Signs and Symptoms; Staging; Surface; Symptoms; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Thrombospondin 1; Tissues; United States; Vision; Wild Type Mouse; Work; adaptive immunity; base; cytokine; in vivo; insight; novel; novel strategies; ocular surface; research study; therapeutic target; uptake

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.

项目摘要 过敏性结膜炎（AC）影响近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保健费用。除了多年生和季节性形式的交流 这可能会降低生活质量，春季或特应交流的先进形式也可能危及视力。 不幸的是，当前的药物治疗仅是瞬时有效的，并且无法取消迹象和 症状。例如，抗组胺药和肥大细胞稳定剂，靶向IgE介导的释放 促炎细胞因子和组胺。但是，这是重要的上游活动而不是 由这些药物靶向，即树突状细胞（DC）刺激T辅助2淋巴细胞。因此，是 针对DC功能的新型策略可能是治疗AC的更好手段。为此， 这些拟议的研究的总体目标是更好地了解结膜（CONJ）DC和机制 用于AC免疫发作。目前据了解，DC源自不同的谱系 产生不同的子集并执行内在或专业功能，而我们实验室的最新工作具有 启动了构成CONJ DC网络的子集的分类和各自的个体基因。这，是 一种，允许与先前在其他粘膜组织中鉴定的DC子集进行比较，例如 构成肺或肠道，也维持过敏性炎症。此外，识别此类DC子集 在CONJ中将促进本研究的目标1，这是为了辨别哪个DC子集在AC和AC中具有免疫发育性 这是否是通过熟练的T细胞刺激和/或增强过敏原的摄取和表现来实现的。 关于由CONJ DC介导的T细胞刺激，此提案中提出的初步研究表明 那个具有免疫调节功能的母细胞糖蛋白（TSP）-1（TSP）-1抑制DC 导致T细胞刺激所需的成熟。因此，本提案的目标2试图探索 TSP-1缺乏AC的免疫发病发生。总而言之，这些研究的结果将进一步提供 了解Conj DC子集和功能，该区域不仅适用于过敏，而且适用于 感染性疾病和其他与眼部表面的免疫相关疾病。此外，识别 AC及其机制中的免疫发育性DC子集中将为重要见解 开发急需的治疗策略来更好地治疗AC。