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Role of Epithelium in Airway Immunity

上皮在气道免疫中的作用

基本信息

批准号：
7919365
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
项目类别：
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/7919365
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 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 eosinophilic inflammation fetal in vivo infancy inhibitor/antagonist lung development nonhuman primate peripheral blood postnatal public health relevance research study response

项目摘要

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)

描述（由申请人提供）：