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.
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.
|Clay, Candice C; Reader, J Rachel; Gerriets, Joan E et al. (2014) Enhanced viral replication and modulated innate immune responses in infant airway epithelium following H1N1 infection. J Virol 88:7412-25|
|Clay, Candice C; Maniar-Hew, Kinjal; Gerriets, Joan E et al. (2014) Early life ozone exposure results in dysregulated innate immune function and altered microRNA expression in airway epithelium. PLoS One 9:e90401|
|Maniar-Hew, Kinjal; Clay, Candice C; Postlethwait, Edward M et al. (2013) Innate immune response to LPS in airway epithelium is dependent on chronological age and antecedent exposures. Am J Respir Cell Mol Biol 49:710-20|
|Tsai, Hsing-Chuan; Wu, Reen (2013) Cholera toxin directly enhances IL-17A production from human CD4+ T cells. J Immunol 191:4095-102|
|Tsai, Hsing-Chuan; Velichko, Sharlene; Hung, Li-Yin et al. (2013) IL-17A and Th17 cells in lung inflammation: an update on the role of Th17 cell differentiation and IL-17R signaling in host defense against infection. Clin Dev Immunol 2013:267971|
|Maniar-Hew, Kinjal; Postlethwait, Edward M; Fanucchi, Michelle V et al. (2011) Postnatal episodic ozone results in persistent attenuation of pulmonary and peripheral blood responses to LPS challenge. Am J Physiol Lung Cell Mol Physiol 300:L462-71|