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在哮喘发病中起作用。 暴露在环境中。早期生活是暴露于哮喘的关键窗口 最近的证据表明，这一窗口期延伸到产前时期。改进 在空调技术使我们能够保持我们的家庭在温度理想的尘螨 增长导致一些人推测螨负荷的增加可能会导致人群中哮喘的增加。 事实上，虽然产前暴露于饮食或宠物来源的过敏原会限制人类的过敏敏感性， 产前屋尘螨（HDM）暴露增加致敏。然而，我们对这些问题的有限认识 母体暴露影响后代哮喘发展的机制，包括它们是否 在产前或产后期间进行手术，是一个关键的知识差距。我们的初步数据显示 妊娠期HDM暴露会导致更严重的HDM诱导的气道高反应性（AHR）， 暴露于HDM的子代中Th 2/Th 17细胞因子的产生和HDM特异性免疫球蛋白（Ig）的合成 妈妈们与其他已发表的模型相反，表明母体OVA（明矾）暴露增加 后代对OVA和不相关过敏原敏感，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）。我们观察到的独特的抗原特异性 直接告知当前应用的首要假设：过敏原和/或过敏原的转移 特定成分（Ig或母体微嵌合细胞（MMCs））负责HDM中AHR的增加。 暴露于HDM的母鼠的后代。在本应用程序中，我们将解决与此相关的关键问题 有两个目的的假设：1）确定妊娠期HDM暴露是否影响哮喘 通过产前或产后机制在后代中的发育，我们将比较AHR、气道 炎症、HDM驱动的Th 2和Th 17细胞因子产生以及阴道或阴道中HDM特异性IG合成 剖腹产分娩出暴露于HDM的母鼠的后代，而对照母鼠的后代则被寄养在 PBS-或HDM-暴露母鼠。2)为了确定暴露于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，我们将 确定在子宫内或母乳中传递的HDM是否会增加后代哮喘的严重程度， 阻止母体Ig的吸附可以逆转所观察到的母体HDM暴露的影响， 评估MMCs耗竭对HDM暴露母鼠后代哮喘发展的影响。的 这项研究的结果将加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，回答了有关机制的主要未解决的问题， 母亲暴露可影响后代哮喘，并提出新的干预措施，以减轻独特的 母体HDM暴露对HDM诱导的过敏性疾病发展的影响。