Early Immune Events in Childhood Asthma

虽然过敏性哮喘的诊断标准通常要到学龄儿童才能达到， 流行病学研究表明，过敏性哮喘的发病机制遵循一个渐进的过程， 在婴儿期。对婴儿肺内的粘膜免疫环境知之甚少。我们 提出新生儿肺是一个免疫学上不同的隔室，经历发育过程， 随着出生后的不断成熟而变化。因此，免疫和结构细胞的发育成熟 肺的组成部分将影响对空气过敏原暴露的整体反应，并可能引发早期过敏反应。 过敏性气道疾病的阶段。本申请的主要目的是确定早期 儿童哮喘临床症状发生的肺机制。我们的发现在 儿童哮喘的幼年灵长类动物模型与变应原诱导的气道高反应性相关， 气道重塑伴气道嗜酸性粒细胞增多，与肺Th 2细胞因子谱无关。此外，本发明还提供了一种方法， 我们已经发现，气道上皮中eotaxin-3/CCL 26的表达与气道炎症的发生显著相关， 嗜酸性粒细胞增多症因此，我们的中心假设是，肺嗜酸性粒细胞增多症， 出生后发育过程中过敏性气道疾病发生的关键第一步;随后 肺T辅助效应物应答的成熟可能是慢性哮喘进展所必需的。 我们进一步假设，嗜酸性粒细胞趋化因子-3/CCL26在吸入过敏原后的嗜酸性粒细胞运输中起主要作用。 婴儿期的暴露。这些假设将通过实验来解决，这些实验将1）确定 肺嗜酸性粒细胞在气道反应性和气道重塑中的作用 2）确定eotaxin-3/CCL 26和eotaxin/CCL 11在出生后发育中的功能作用， 在婴儿期嗜酸性粒细胞的募集，和3）确定发育和分子调控， Eotaxin-3/CCL 26在气道上皮中的表达。

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 hypothesis 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.