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.

过敏性哮喘的发病率正在以与纯遗传病因不一致的速度增加，这表明过敏性哮喘的发病率 用于环境暴露。生命早期是一个暴露可能影响哮喘的关键时期 发育，最近的证据表明这个窗口延伸到产前时期。改进 空调技术使我们能够将家中的温度维持在适合尘螨生长的温度 增长导致一些人推测螨虫数量的增加可能会导致人口中哮喘的增加。 事实上，虽然产前接触饮食或宠物衍生的过敏原会限制人类的过敏反应， 产前屋尘螨 (HDM) 暴露会增加过敏性。然而，我们的知识有限 母亲接触影响后代哮喘发展的机制，包括是否 在产前或产后时期进行操作是一个关键的知识差距。我们的初步数据表明 怀孕期间暴露于 HDM 会导致更严重的 HDM 诱发的气道高反应性 (AHR)， 暴露后代中 Th2/Th17 细胞因子的产生以及 HDM 特异性免疫球蛋白 (Igs) 的合成 妈妈们。与其他已发表的模型相比，表明母亲 OVA（明矾）暴露量增加 后代对 OVA 和无关过敏原均敏感，母体 HDM 暴露不会增加敏感性 不相关的呼吸道过敏原（烟曲霉）。我们观察到的独特抗原特异性 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（Igs 或母体微嵌合细胞 (MMcs)）是导致 HDM-AHR 增加的原因 暴露于 HDM 的水坝的后代受到挑战。在此应用程序中，我们将解决与此相关的关键问题 假设有两个目的：1) 确定妊娠期间暴露于 HDM 是否会影响哮喘 通过产前或产后机制对后代进行发育，我们将比较 AHR、气道 炎症、HDM 驱动的 Th2 和 Th17 细胞因子产生以及阴道或阴道中的 HDM 特异性 Ig 合成 剖腹产产生了暴露于 HDM 的母鼠的后代，以及在对照母鼠上培育的后代 暴露于 PBS 或 HDM 的水坝。 2) 确定暴露于 HDM 的后代是否会出现更严重的 AHR 通过转移过敏原或母体适应性免疫系统的成分来消除母体，我们将 确定子宫内或母乳喂养的 HDM 是否会增加后代哮喘的严重程度，确定是否 防止母体 Igs 的吸附可以逆转母体 HDM 暴露所观察到的影响，并且 评估 MMcs 耗竭对暴露于 HDM 的母鼠后代哮喘发展的影响。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问题 母亲接触可能影响后代哮喘，并建议采取新的干预措施来减轻独特的影响 母亲 HDM 暴露对 HDM 诱发的过敏性疾病发展的影响。