Role of Epithelium in Airway Immunity

关于人类婴儿肺内发生的先天事件，人们知之甚少 在生命后期对吸入过敏原的病理免疫反应的发展。我们不知道是否 婴儿肺的结构细胞可以显著影响免疫反应的表型 一个令人窒息的环境挑战。具有特殊意义的是传导的上皮细胞。 Airways，在架构和功能上都准备好充当适应性免疫的联络人 系统。这项建议的主要目标是确定传导的呼吸道上皮如何 婴幼儿肺的损伤会影响对吸入变应原的适应性免疫反应。我们的整体 假说认为婴儿肺上皮细胞在哮喘的发病中起中心作用。 表型，通过结构性CCL20趋化因子表达促进呼吸道招募 趋化因子受体CCR6+T淋巴细胞。这一假设是基于获得的初步数据。 来自呼吸道上皮细胞培养，表现出年龄依赖性的表达和抑制 MicroRNA通过IL-17A对CCL20的调节我们还发现了一群产生IL-17A的细胞 过敏原暴露幼猴呼吸道CCR6+T淋巴细胞的研究鉴于人类的树突状细胞 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通过Th2/Th1细胞因子的失衡来调节的， 而是IL-17A/IL-12失衡。为了检验这些假设，我们将1)调查 婴幼儿呼吸道上皮细胞CCL20表达的发育性调控2)趋化因子的特性 变应原暴露后幼猴肺中受体CCR6+淋巴细胞群，以及 3)确定IL-17/IL-12失衡对过敏原暴露的幼猴的影响。这个 本应用程序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可以指导病理免疫的发展。 对吸入过敏原的反应。我们关于IL-17A在骨肉瘤发生发展中的作用的研究结果 哮喘在非人类灵长类动物中可以直接外推以确定候选 预防儿童哮喘的药物。

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.