Role of Epithelium in Airway Immunity

上皮在气道免疫中的作用

• 批准号: 7714083
• 负责人: Lisa A Miller
• 金额: $ 38.33万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7714083
• 关键词: Adult; Allergens; Animal Model; Animals; Aspirate substance; Asthma; Attenuated; Biological Assay; Breathing; CCL20 gene; CCR6 gene; Cell Culture Techniques; Cells; Cellular biology; Childhood; Childhood Asthma; Chronic Disease; Clinical; Data; Dendritic Cells; Development; Environment; Epithelial Cells; Epithelium; Ethics; Event; Flow Cytometry; Goals; Human; Immune; Immune response; Immune system; Immunity; Immunobiology; Immunophenotyping; In Vitro; Infant; Inflammation; Interleukin-12; Interleukin-17; Laboratories; Life; Lung; Lymphocyte; Macaca mulatta; Measures; Mediating; MicroRNAs; Modeling; Monkeys; Mucosal Immune Responses; Neonatology; Pathologic; Phase; Phenotype; Play; Population; Positioning Attribute; Predisposition; Prevention; Primary Cell Cultures; Recombinants; Recruitment Activity; Regulation; Research; Resources; Role; Route; Staging; T-Lymphocyte; Testing; abstracting; age related; airway epithelium; airway hyperresponsiveness; base; candidate identification; chemokine; chemokine receptor; comparative; cytokine; developmental immunology; drug candidate; fetal; in vivo; infancy; inhibitor/antagonist; lung development; nonhuman primate; peripheral blood; postnatal; public health relevance; research study; response

DESCRIPTION (provided by applicant): Little is known about the antecedent events within the human infant lung that predispose the development of pathologic immune responses to inhaled allergens later in life. We do not know if the structural cells of the infant lung can significantly influence the phenotype of an immune response to an inhaled environmental challenge. Of particular significance is the epithelial cell of the conducting airways, which is architecturally and functionally poised to serve as a liaison to the adaptive immune system. The primary objective of this proposal is to determine how the conducting airway epithelium of the infant lung can influence the adaptive immune response to inhaled allergens. Our overall hypothesis is that epithelial cells of the infant lung play a central role in the initiation of the asthma phenotype, via constitutive CCL20 chemokine expression to promote airways recruitment of chemokine receptor CCR6+ T lymphocytes. This hypothesis is based on preliminary data obtained from airway epithelial cell cultures, demonstrating age-dependent expression and inhibitory microRNA regulation of CCL20 via IL-17A. We have also identified a population of IL-17A-producing CCR6+ T lymphocytes in airways of allergen-exposed infant monkeys. Given that human dendritic cells are deficient in IL-12 (a potent inhibitor of IL-17A) during infancy, we further hypothesize that development of the asthma phenotype is initially mediated not by an imbalance of Th2/Th1 cytokines, but rather an imbalance of IL-17A/IL-12. To test these hypotheses, we will 1) investigate the developmental regulation of CCL20 expression in infant airway epithelium, 2) characterize chemokine receptor CCR6+ lymphocyte populations in the infant monkey lung following allergen exposure, and 3) determine the impact of IL-17/IL-12 imbalance on allergen exposed infant monkeys. The experiments proposed within this application will contribute to our overall understanding of how the epithelium of the maturing postnatal lung can direct the development of a pathologic immune response to inhaled allergens. Our findings regarding the contribution of IL-17A in development of asthma in the non-human primate can be directly extrapolated towards identification of candidate drugs for the prevention of childhood asthma. PUBLIC HEALTH RELEVANCE: The experiments proposed within this application will contribute to our overall understanding of how the epithelium of the maturing postnatal lung can direct the development of a pathologic immune response to inhaled allergens. Our findings regarding the contribution of IL-17A in the development of the asthma phenotype in non-human primates can be directly extrapolated towards identification of candidate drugs for the prevention of childhood asthma. (End of Abstract)

描述(由申请人提供)： 人们对人类婴儿肺内的先期事件知之甚少，这些事件有利于在以后的生活中对吸入性变应原产生病理免疫反应。我们不知道婴儿肺的结构细胞是否能显著影响对吸入环境挑战的免疫反应的表型。特别重要的是传导呼吸道的上皮细胞，它在结构上和功能上都准备好作为适应性免疫系统的联络人。这项建议的主要目的是确定婴儿肺的传导呼吸道上皮如何影响对吸入性变应原的适应性免疫反应。我们的总体假设是，婴儿肺上皮细胞通过结构性CCL20趋化因子的表达促进趋化因子受体CCR6+T淋巴细胞的呼吸道募集，在哮喘表型的启动中发挥核心作用。这一假说是基于从呼吸道上皮细胞培养中获得的初步数据，证明了CCL20的年龄依赖性表达和通过IL-17A抑制的microRNA调节。我们还在暴露于过敏原的幼猴的呼吸道中发现了一群产生IL-17A的CCR6+T淋巴细胞。鉴于人类树突状细胞在婴儿期缺乏IL-12(一种有效的IL-17A抑制物)，我们进一步假设哮喘表型的发展最初不是由Th2/Th1细胞因子的失衡介导的，而是IL-17A/IL-12的失衡所致。为了验证这些假设，我们将1)研究婴儿呼吸道上皮细胞CCL20表达的发育规律，2)研究变应原暴露后婴儿猴肺中趋化因子受体CCR6+淋巴细胞的特征，3)确定IL-17/IL-12失衡对暴露于变应原的幼猴的影响。在这一应用中提出的实验将有助于我们全面了解成熟的出生后肺上皮如何指导对吸入性变应原的病理免疫反应的发展。我们关于IL-17A在非人类灵长类动物哮喘发病中的作用的发现可以直接推断为确定预防儿童哮喘的候选药物。 公共卫生相关性：本申请中提出的实验将有助于我们全面了解成熟的出生后肺上皮如何指导对吸入性过敏原的病理免疫反应的发展。我们关于IL-17A在非人类灵长类动物哮喘表型发展中的作用的发现，可以直接推断为确定预防儿童哮喘的候选药物。(摘要结束)