Role of Epithelium in Airway Immunity

描述（由申请人提供）： 对人类婴儿肺内的前驱事件知之甚少，这些事件易导致日后对吸入性过敏原的病理性免疫反应的发展。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。特别重要的是传导气道的上皮细胞，其在结构上和功能上准备充当与适应性免疫系统的联络。这项建议的主要目的是确定婴儿肺的气道上皮细胞如何影响对吸入性过敏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组成性CCL 20趋化因子表达促进气道募集趋化因子受体CCR 6 + T淋巴细胞，在哮喘表型的起始中起核心作用。这一假设是基于从气道上皮细胞培养物获得的初步数据，证明了CCL 20的年龄依赖性表达和通过IL-17 A的抑制性microRNA调节。我们还确定了一个人口的IL-17 A产生CCR 6 + T淋巴细胞在过敏原暴露的幼猴的气道。鉴于人类树突状细胞在婴儿期缺乏IL-12（一种有效的IL-17 A抑制剂），我们进一步假设哮喘表型的发展最初不是由Th 2/Th 1细胞因子的失衡介导的，而是IL-17 A/IL-12的失衡。为了验证这些假设，我们将1）研究婴儿气道上皮细胞中CCL 20表达的发育调节，2）描述过敏原暴露后婴儿猴肺中趋化因子受体CCR 6+淋巴细胞群的特征，3）确定IL-17/IL-12失衡对过敏原暴露的婴儿猴的影响。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的上皮细胞如何指导对吸入性过敏原的病理性免疫应答的发展。我们关于IL-17 A在非人灵长类动物哮喘发生中的作用的研究结果可以直接外推到用于预防儿童哮喘的候选药物的鉴定。 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的上皮细胞如何指导对吸入性过敏原的病理性免疫应答的发展。我们关于IL-17 A在非人灵长类动物哮喘表型发展中的作用的研究结果可以直接外推到用于预防儿童哮喘的候选药物的鉴定。(End摘要）

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)