Although the diagnostic criteria for allergic asthma are typically not fulfilled until children are of school age, epidemiologic studies suggest that the pathogenesis of allergic asthma follows a progressive course starting at infancy. Little is known about the mucosal immune environment within the infant human lung. We propose that the newborn lung is an immunologically distinct compartment that undergoes developmental shifts with ongoing postnatal maturation. As such, developmental maturity of the immune and structural cell constituents of the lung will affect the overall response to aeroallergen exposure and may initiate the early stages of allergic airways disease. The primary objective of this application is to determine the early pulmonary mechanisms that initiate development of clinical symptoms in childhood asthma. Our findings in an infant primate model of childhood asthma correlate allergen-induced airway hyperresponsiveness and airways remodeling with airways eosinophilia, independent of a pulmonary Th2 cytokine profile. In addition, we have found that the expression of eotaxin-3/CCL26 within airway epithelium is significantly associated with eosinophilia following allergen challenge. Thus, our central hypothesis is that pulmonary eosinophilia is a critical first step in the initiation of allergic airways disease during postnatal development; subsequent maturation of pulmonary T helper effector responses may be required for progression to chronic asthma. We further postulate that eotaxin-3/CCL26 plays a major role in eosinophil trafficking following aeroallergen exposures during infancy. These hypotheses will be addressed by experiments which will 1) determine the functional role for lung eosinophils in the development of airways reactivity and airways remodeling during postnatal development, 2) define the functional role of eotaxin-3/CCL26 and eotaxin/CCL11 in the recruitment of eosinophils during infancy, and 3) determine the developmental and molecular regulation of eotaxin-3/CCL26 in airway epithelium. ? ? ?
