Epithelial Regulation of Th2 Immune Responses in the Lung

肺中 Th2 免疫反应的上皮调节

基本信息

批准号：
7696785
负责人：
Marsha Wills-Karp
金额：
$ 37.9万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
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/7696785
关键词：
Allergens Allergic Antigens Asthma Attenuated Automobile Driving Binding Bone Marrow Breathing Bronchoalveolar Lavage CCL20 gene CCR6 gene Cell Differentiation process Cell surface Chemotactic Factors Chloride Ion Chronic Disease Chronic lung disease Complex Data Dendritic Cells Dendritic cell activation Dermatophagoides pteronyssinus antigen p 1 Development Disease Environment Eosinophilia Epithelial Epithelial Cells Etiology Event Extracellular Matrix Extrinsic asthma Feedback Generations Glucans House Dust Mite Allergens IgE Immune response Immunity In Vitro Individual Inflammation Inflammatory Response Interleukin-13 Investigation Lead Lung Maintenance Mediating Mediator of activation protein Molecular Mus Myelogenous Particulate Matter Pathway interactions Pattern Recognition Pattern recognition receptor Peptide Hydrolases Play Production Proteins Pyroglyphidae Recruitment Activity Regulation Role SYK gene Series Signal Pathway Signal Transduction Signaling Molecule Site Staging Surface T-Lymphocyte Testing Th2 Cells airborne allergen airway epithelium airway hyperresponsiveness airway inflammation airway obstruction airway remodeling antigen processing beta-Glucans conditioning cytokine dectin 1 effective therapy immunogenic in vivo lymph nodes mouse model novel public health relevance receptor response syndecan

项目摘要

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，近几十年来一直在增加。尽管哮喘的病因尚不清楚，但目前被认为是由于CD4介导的炎症反应对易感个体的空气生物过敏原的介导的炎症反应而引起的。尽管进行了广泛的研究，但哮喘患者中造成Th2（IL-13）免疫反应的确切机制尚不清楚。 Th2免疫反应的起始和维持取决于气道表面的树突状细胞的特异性激活。最近的证据表明，树突状细胞（DC）的特定亚群对于启动过敏性气道反应至关重要，并且在驱动免疫力（髓样，MDC）或耐受性（浆细胞类动物，PDC）中发挥重要作用。然而，尚不清楚将特定的DC子集募集到肺部并因过敏原暴露而激活的机制尚不清楚。我们的初步数据共同支持了这样一个新的假设，即常见的过敏原，房屋粉尘螨会触发未成熟的树突状细胞化学吸引剂CCL20的快速释放，通过其在dectin necition Molecule的激活（一种识别beta beta-glucans ceptiation Molecule）的激活，从其细胞外基质分子syndecan-1上的储存位点触发。 CCL20曾经释放，驱动了免疫原性树突状细胞子群的优先募集和激活，后者又指导Th2细胞分化和过敏性炎症的发展。此外，IL-13本身可以诱导CCL20从气道上皮释放，从而为持续的Th2细胞因子产生提供放大环。驱动上皮CCL20从Syndecan释放的分子机制，CCL20/Syndecan-1优先募集和激活MDC的机制，IL-13诱导CCL20释放的机制，并诱导CCL20释放并永久募集树突状细胞在这些路径中募集到肺部，并促进了空中的空中渗透到杂物，并构成了杂物的空中渗透到杂物的杂物。未知。因此，我们提出以下特定旨在检验该假设并定义了过敏原诱导的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释放中的作用。 2）确定syndecan-1调节T细胞IL-13产生体外和体内产生的树突状细胞条件的机制； 3）确定IL-13使免疫原性DC亚群募集和进一步的Th2细胞因子产生的机制。总的来说，这些研究的结果应更好地理解驱动Th2（IL-13）细胞因子产生的机制，并可能导致新型哮喘疗法的发展，这些哮喘正在改变而不是改善。公共卫生相关性：哮喘是肺部的一种慢性疾病，近几十年来一直在增加。由于IL-13已被证明是过敏性炎症的中心介体，因此该提案的研究旨在阐明导致肺中IL-13产生的途径。识别发起这些反应的特定途径可能会导致新的有效疗法的发展，以治疗这种不断增长的疾病。