Early Immune Events in Childhood Asthma

描述（由申请人提供）：虽然过敏性哮喘的诊断标准通常在学龄儿童之前不符合，但流行病学研究表明过敏性哮喘的发病机制从婴儿期开始呈渐进性过程。对婴儿肺内的粘膜免疫环境知之甚少。我们认为，新生儿肺是一个免疫学上不同的隔室，经历了不断的出生后成熟的发展变化。因此，肺的免疫和结构细胞成分的发育成熟将影响对空气过敏原暴露的总体反应，并可能引发过敏性气道疾病的早期阶段。本申请的主要目的是确定儿童哮喘临床症状发生的早期肺部机制。我们在一个幼年灵长类动物的儿童哮喘模型中的研究结果表明，过敏原诱导的气道高反应性和气道重塑与气道嗜酸性粒细胞增多相关，而与肺Th 2细胞因子谱无关。此外，我们发现气道上皮内嗜酸性粒细胞趋化因子-3/CCL26的表达与过敏原激发后的嗜酸性粒细胞增多显著相关。因此，我们的中心假设是，肺嗜酸性粒细胞增多症是一个关键的第一步，在过敏性气道疾病的启动在出生后的发展，随后成熟的肺辅助性T细胞效应器的反应可能需要进展为慢性哮喘。我们进一步假设，嗜酸性粒细胞趋化因子-3/CCL26在婴儿期吸入过敏原暴露后嗜酸性粒细胞运输中起主要作用。这些假设将通过实验来解决，所述实验将1）确定肺嗜酸性粒细胞在出生后发育期间气道反应性和气道重塑的发展中的功能作用，2）确定嗜酸性粒细胞活化趋化因子-3/CCL26和嗜酸性粒细胞活化趋化因子/CCL 11在婴儿期间嗜酸性粒细胞募集中的功能作用，和3）确定嗜酸性粒细胞活化趋化因子-3/CCL26在气道上皮中的发育和分子调节。

DESCRIPTION (provided by applicant): 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.