Early Immune Events in Childhood Asthma

儿童哮喘的早期免疫事件

基本信息

批准号：
7571624
负责人：
Lisa A Miller
金额：
$ 29.32万
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：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7571624
关键词：
Acute Address Adult Affect Allergens American Animal Model Asthma Autoimmune Diseases Birth Breathing California Cell Culture Techniques Cells Child Childhood Childhood Asthma Chronic Chronic Disease Clinical Clinical Trials Comparative Study Data Development Diagnostic Disease Environment Environmental Exposure Eosinophilia Eotaxin Epidemiologic Studies Ethics Event Exhibits Extrinsic asthma Family member Generations Goals Housing Human Immune Immune response Immune system Immunobiology Immunology Infant Interleukin-5 Irrigation Kinetics Laboratories Laboratory Animals Lung Macaca mulatta Mediating Messenger RNA Mites Modeling Molecular Monkeys Morbidity - disease rate Mus Neonatal Newborn Infant Outcome Pathogenesis Pathway interactions Phase Play Positioning Attribute Predisposition Prevention Primates Procedures Process Proteinase-Activated Receptors Pulmonary Eosinophilia Pyroglyphidae Regulation Relative (related person)Research Research Personnel Rodent Rodent Model Role School-Age Population Staging Structure Symptoms T-Lymphocyte Testing Thymectomy airborne allergen airway epithelium airway hyperresponsiveness airway remodeling allergic airway disease base candidate identification chemokine comparative cytokine drug candidate drug development eosinophil epidemiology study human CCL26 protein humanized monoclonal antibodies immunoregulation infancy lung development lung maturation mepolizumab nonhuman primate postnatal protein expression research study response trafficking

项目摘要

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.

尽管过敏性哮喘的诊断标准通常直到儿童年龄，但流行病学研究表明，过敏性哮喘的发病机理遵循渐进的过程婴儿期。关于婴儿肺中的粘膜免疫环境知之甚少。我们提出新生儿肺是一种免疫学上不同的隔室，可进行发育随着持续的产后成熟而转移。因此，免疫和结构细胞的发育成熟度肺的成分将影响对航空过敏烯暴露的总体反应，并可能提早启动过敏气道疾病的阶段。该应用的主要目的是确定早期在儿童哮喘中启动临床症状发展的肺机制。我们的发现儿童哮喘的婴儿灵长类动物模型与过敏原诱导的气道高反应性和气道用气道嗜酸性粒细胞重塑，与肺Th2细胞因子谱无关。此外，我们发现，气道上皮中eotaxin-3/ccl26的表达显着相关在过敏原挑战之后，嗜酸性粒细胞菌。因此，我们的中心假设是肺嗜酸性粒细胞是产后发育期间开始过敏性气道疾病的关键第一步；随后的向慢性哮喘进展可能需要肺T辅助效应子反应的成熟。我们进一步指出，eotaxin-3/ccl26在嗜酸果过敏烯后在嗜酸性粒细胞运输中起主要作用婴儿期暴露。这些假设将通过实验来解决，该实验将确定肺嗜酸性粒细胞在气道反应性和气道重塑过程中的功能作用产后发展，2）定义eotaxin-3/ccl26和eotaxin/ccl11在该功能的作用婴儿期间嗜酸性粒细胞的募集，以及3）确定的发育和分子调节气道上皮中的eotaxin-3/ccl26。