Epithelial Regulation of Th2 Immune Responses in the Lung

肺中 Th2 免疫反应的上皮调节

• 批准号: 8443938
• 负责人: Marsha Wills-Karp
• 金额: $ 26.45万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-20 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8443938
• 关键词: Epithelial; Regulation; Th2; Immune; Responses

DESCRIPTION (provided by applicant): Allergic asthma is a chronic disease which has been on the rise in recent decades. Although the etiology of asthma is not well understood, it is currently thought to arise as a result of inappropriate CD4?mediated inflammatory responses to airborne allergens in susceptible individuals. Despite extensive investigation, the exact mechanisms responsible for the initiation of Th2 (IL-13) immune responses in asthmatic individuals are unknown. The initiation and maintenance of Th2 immune responses are dependent upon specific activation of dendritic cells at the airway surface. Recent evidence suggests that specific subsets of dendritic cells (DCs) are critical for the initiation of allergic airway responses and play an important role in driving either immunity (myeloid, mDCs) or tolerance (plasmacytoid, pDCs) to inhaled antigens. However, the mechanisms by which specific DC subsets are recruited to the lung and activated in response to allergen exposure are unknown. Our preliminary data collectively support the novel hypothesis that the common allergen, house dust mite, triggers the rapid release of the immature dendritic cell chemoattractant, CCL20, from its storage sites on the extracellular matrix molecule syndecan-1, through the activation of dectin-1, a pattern recognition molecule which recognizes beta-glucans. CCL20 once released drives the preferential recruitment and activation of the immunogenic myeloid dendritic cell subset which in turn directs Th2 cell differentiation and the development of allergic inflammation. Moreover, IL-13 itself can induce the release of CCL20 from the airway epithelium providing an amplication loop for continued Th2 cytokine production. The molecular mechanisms driving epithelial CCL20 release from syndecan, the mechanisms of preferential recruitment and activation of mDCs by CCL20/syndecan-1, the mechanisms by which IL-13 induces CCL20 release and perpetuates dendritic cell recruitment into the lung, and the exact contributions of these pathways to allergen-induced airway hyperresponsiveness and airway inflammation are unknown. Thus we propose the following specific aims to test this hypothesis and define the molecular mechanisms underlying allergen-induced induction of Th2 cytokine production: 1)To determine the role of dectin-1 signaling pathways in the HDM-induced release of syndecan-1/CCL20 complexes from the surface of airway epithelial cells; 2) To determine the mechanism by which syndecan-1 regulates dendritic cell conditioning of T cell IL- 13 production in vitro and in vivo; 3)To determine the mechanisms by which IL-13 perpetuates the recruitment of immunogenic DC subsets and further Th2 cytokine production. Collectively, the results of these studies should provide a better understanding of the mechanisms driving Th2 (IL-13) cytokine production and may lead to the development of novel asthma therapies which are disease modifying rather than ameliorative. PUBLIC HEALTH RELEVANCE: Asthma is a chronic disease of the lung which has been on the rise in recent decades. As IL-13 has been shown to be a central mediator of allergic inflammation, studies in this proposal aim to elucidate the pathways leading to the generation of IL-13 in the lung. The identification of specific pathways initiating these responses may lead to the development of novel, effective therapies for the treatment of this ever-increasing disease.

描述（由申请人提供）： 过敏性哮喘是一种慢性疾病，近几十年来呈上升趋势。虽然哮喘的病因尚不清楚，但目前认为其是易感个体对空气中过敏原不适当的CD4介导的炎症反应的结果。尽管进行了广泛的研究，但哮喘患者中引发 Th2 (IL-13) 免疫反应的确切机制尚不清楚。 Th2 免疫反应的启动和维持依赖于气道表面树突状细胞的特异性激活。最近的证据表明，树突状细胞 (DC) 的特定亚群对于过敏性气道反应的启动至关重要，并且在驱动对吸入抗原的免疫（髓样，mDC）或耐受（浆细胞，pDC）方面发挥重要作用。然而，特定 DC 亚群被招募到肺部并响应过敏原暴露而被激活的机制尚不清楚。我们的初步数据共同支持了新的假设，即常见的过敏原屋尘螨通过激活dectin-1（一种识别β-葡聚糖的模式识别分子），触发未成熟树突状细胞趋化剂CCL20从细胞外基质分子syndecan-1上的储存位点快速释放。 CCL20 一旦释放，就会驱动免疫原性骨髓树突状细胞亚群的优先招募和激活，进而指导 Th2 细胞分化和过敏性炎症的发展。此外，IL-13 本身可以诱导气道上皮释放 CCL20，为持续 Th2 细胞因子的产生提供扩增循环。驱动上皮CCL20从syndecan释放的分子机制、CCL20/syndecan-1优先招募和激活mDC的机制、IL-13诱导CCL20释放和使树突状细胞永久招募到肺部的机制，以及这些途径对过敏原诱导的气道高反应性和气道炎症的确切贡献是 未知。因此，我们提出以下具体目标来检验这一假设并定义过敏原诱导的 Th2 细胞因子产生的分子机制： 1）确定 dectin-1 信号通路在 HDM 诱导的 syndecan-1/CCL20 复合物从气道上皮细胞表面释放中的作用； 2) 确定syndecan-1在体外和体内调节树突状细胞调节T细胞IL-13产生的机制； 3)确定IL-13持续招募免疫原性DC亚群和进一步产生Th2细胞因子的机制。总的来说，这些研究的结果应该可以更好地理解驱动 Th2 (IL-13) 细胞因子产生的机制，并可能导致开发出改变疾病而不是改善疾病的新型哮喘疗法。公共卫生相关性：哮喘是一种慢性肺部疾病，近几十年来发病率呈上升趋势。由于 IL-13 已被证明是过敏性炎症的中心介质，因此本提案中的研究旨在阐明导致肺部产生 IL-13 的途径。识别引发这些反应的特定途径可能会导致开发出新的、有效的疗法来治疗这种不断增加的疾病。