Impact of prenatal HDM exposure in severely asthmatic mothers on offspring asthma

严重哮喘母亲产前暴露于 HDM 对后代哮喘的影响

• 批准号: 9243430
• 负责人: Ian Paul Lewkowich
• 金额: $ 29.13万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243430
• 关键词: Adaptive Immune System; Address; Adsorption; Air Conditioning; Allergens; Allergic; Allergic Disease; Amniotic Fluid; Animal Model; Antibodies; Antigens; Applications Grants; Aspergillus; Asthma; Atopic Dermatitis; Automobile Driving; Biological Response Modifiers; Birth; Cells; Cesarean section; Child; Cohort Effect; Data; Development; Diet; Disease; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Exposure to; Extrinsic asthma; Fostering; Future; Genetic Models; Genetic Predisposition to Disease; Growth; Home environment; Home heating; House Dust Mite Allergens; Human; Human Milk; Humidity; IgE; Immune; Immune response; Immunoglobulins; Incidence; Inflammatory Response; Interferon Type II; Intervention; Knowledge; Life; Maternal Exposure; Mediating; Mites; Modality; Modeling; Mothers; Mus; Population; Pregnancy; Prevalence; Production; Publishing; Pyroglyphidae; Reporting; Risk; Risk Factors; Role; Severities; Specificity; System; Technology; Temperature; Testing; Umbilical Cord Blood; Vagina; Work; airborne allergen; airway hyperresponsiveness; airway inflammation; allergic response; asthmatic; cytokine; early life exposure; in utero; indoor allergen; innovation; mouse model; neonatal Fc receptor; novel; offspring; ovalbumin-alum; postnatal; pregnant; prenatal; prenatal exposure; prevent; pup; pyroglyphid; respiratory; response; therapy design

The incidence of allergic asthma is increasing at rates inconsistent a purely genetic etiology, suggesting a role for environmental exposures. Early life represents a critical window in which exposure can influence asthma development, and recent evidence suggests that this window extends into the prenatal period. Improvements in air-conditioning technology have allowed us to maintain our homes at temperatures ideal for dust mite growth leading some to speculate that increased mite load may drive increased asthma in the population. Indeed, while prenatal exposure to dietary or pet-derived allergens drive limit allergic sensitization in humans, prenatal house dust mite (HDM) exposure increases sensitization. However, our limited knowledge of the mechanisms whereby maternal exposures influence offspring asthma development, including whether they operate in the pre- or post-natal periods, represent a key knowledge gap. Our preliminary data demonstrate that HDM exposure in pregnancy drives more severe HDM-induced airway hyperresponsiveness (AHR), Th2/Th17 cytokine production, and synthesis of HDM-specific immunoglobulins (Igs) in offspring of exposed mothers. In contrast to other published models demonstrating that maternal OVA (alum) exposures increases offspring sensitivity to both OVA and unrelated allergens, maternal HDM exposure does not increase sensitivity to unrelated respiratory allergens (Aspergillus fumigatus). The unique antigen-specificity of our observations directly inform the overarching hypothesis of the current application: that transfer of allergens and/or allergen specific components (Igs or maternal microchimeric cells (MMcs) are responsible for increased AHR in HDM- challenged offspring of HDM-exposed dams. In this application we will address key questions related to this hypothesis in two aims: 1) to determine if HDM exposure during pregnancy influences asthma development in offspring through prenatal or postnatal mechanisms, we will compare AHR, airway inflammation, HDM-driven Th2 and Th17 cytokine production and HDM-specific Ig synthesis in vaginally or cesarean section delivered offspring of HDM-exposed dams, and in offspring of control dams fostered onto PBS- or HDM-exposed dams. 2) To determine if more severe AHR develops in offspring of HDM-exposed dams through transfer of allergen or components of the maternal adaptive immune system, we will determine if in utero or breast-milk delivered HDM can increase the severity of offspring asthma, determine if preventing adsorption of maternal Igs can reverse the observed effects of maternal HDM exposure, and assess the impact of depletion of MMcs on asthma development in offspring of HDM-exposed dams. The results of this study will enhance our understanding of factors that influence the development of the immune responses that cause allergic asthma, answer major unresolved questions about mechanisms through which maternal exposures can influence offspring asthma, and suggest novel interventions to mitigate the unique effects of maternal HDM exposure on the development of HDM-induced allergic diseases.

过敏性哮喘的发生率正在以不一致的纯粹遗传病因的速度增加，这表明作用 环境暴露。早期生活是一个关键的窗口，暴露会影响哮喘 开发和最近的证据表明，该窗口扩展到产前时期。改进 在空调技术中，使我们能够保持房屋的温度，非常适合尘螨 增长导致一些人推测，螨虫负荷增加可能会增加人群的哮喘。 确实，虽然产前暴露于饮食或宠物衍生的过敏原驱动器限制了人类的过敏反应，但 产前房屋尘螨（HDM）暴露会增加敏感性。但是，我们对 孕产妇暴露会影响后代哮喘的发展的机制，包括它们是否是否 在产前或产后时期操作，代表关键知识差距。我们的初步数据证明了 怀孕中的HDM暴露驱动了更严重的HDM引起的气道高反应性（AHR）， Th2/Th17细胞因子的产生和HDM特异性免疫球蛋白（IGS）的合成 母亲。与其他已发表的模型相反，表明母体OVA（明矾）暴露会增加 后代对OVA和不相关过敏原的敏感性，母体HDM暴露不会增加灵敏度 到无关的呼吸过敏原（曲霉）。我们观察的独特抗原特异性 直接告知当前应用的总体假设：过敏原和/或过敏原的转移 特定成分（Ig或母体微chimeric细胞（MMC）负责HDM-的AHR增加 挑战了暴露于HDM的大坝的后代。在此应用程序中，我们将解决与此相关的关键问题 两个目标的假设：1）确定怀孕期间的HDM暴露是否影响哮喘 通过产前或产后机制开发后代，我们将比较AHR，气道 在阴道或 在 PBS或HDM暴露的大坝。 2）确定在暴露于HDM的后代时是否会出现更严重的AHR 大坝通过过敏原或母体自适应免疫系统的成分的转移，我们将 确定在子宫内或乳房中递送的HDM是否可以增加后代哮喘的严重程度，确定是否是否 防止母体IG的吸附可以扭转观察到的母体HDM暴露的影响，并扭转 评估MMC耗尽对HDM暴露大坝后代哮喘发育的影响。这 这项研究的结果将增强我们对影响免疫发展的因素的理解 引起过敏性哮喘的反应，回答有关机制的主要未解决的问题 孕产妇的暴露会影响后代哮喘，并提出新颖的干预措施以减轻独特 母体HDM暴露对HDM诱导的过敏性疾病发展的影响。