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

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
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-12-01 至 2018-11-30

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中文摘要
翻译
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,这表明了一个作用 因为暴露在环境中。早年生活是一个关键的窗口,在这个窗口中暴露会影响哮喘 发展,最近的证据表明,这一窗口延伸到产前阶段。改进 空调技术使我们能够将我们的家保持在最适合尘螨的温度 增长导致一些人推测,增加的尘螨载量可能会导致人口中哮喘的增加。 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反应, 产前接触室内粉尘(HDM)会增加敏感度。然而,我们对此的有限了解 母亲暴露影响子代哮喘发展的机制,包括它们是否 在产前或产后阶段工作,代表着关键的知识差距。我们的初步数据显示 怀孕期间接触HDM会导致更严重的HDM诱导的呼吸道高反应性(AHR), 接触工人子代Th2/Th17细胞因子的产生及HDM特异性免疫球蛋白的合成 母亲们。与其他已发表的模型不同的是,母体接触OVA(明矾)会增加 子代对卵清蛋白和无关变应原的敏感性,母亲接触HDM不会增加敏感性 对不相关的呼吸道变应原(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(免疫球蛋白或母体微嵌合体细胞)是HDM患者AHR升高的原因。 暴露在HDM中的水坝的后代受到挑战。在本申请中,我们将解决与此相关的关键问题 假设有两个目的:1)确定孕期接触HDM是否会影响哮喘 通过出生前或出生后机制的后代发育,我们将比较AHR,呼吸道 炎症、HDM驱动的Th2和Th17细胞因子的产生以及HDM特异性免疫球蛋白的合成 剖腹产产下了暴露于HDM的母鸡的后代,以及饲养在 暴露在PBS或HDM下的大坝。2)确定接触HDM的子代是否会出现更严重的AHR 通过转移变应原或母体适应性免疫系统的组件,我们将 确定在子宫或母乳中分娩的HDM是否会增加后代哮喘的严重程度,确定 预防母体免疫球蛋白的吸附可以逆转观察到的母体接触HDM的影响,以及 评估MMCs耗竭对暴露于HDM的水坝子代中哮喘发生的影响。这个 这项研究的结果将加深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,回答关于以下机制的主要悬而未决的问题 母亲的暴露可以影响后代哮喘,并建议采取新的干预措施来缓解独特的 母亲接触HDM对HDM致变态反应性疾病发生的影响。
英文摘要
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.
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Airway inflammation and fear: neuroimmune mechanisms and forebrain circuits
  • 批准号:
    10668648
  • 项目类别:
  • 资助金额:
    $35.09万
  • 财政年份:
    2022
  • 负责人:
    Ian Paul Lewkowich
  • 依托单位:
Airway inflammation and fear: neuroimmune mechanisms and forebrain circuits
  • 批准号:
    10677767
  • 项目类别:
  • 资助金额:
    $31.99万
  • 财政年份:
    2022
  • 负责人:
    Ian Paul Lewkowich
  • 依托单位:
Preconceptual paternal allergen exposure, offspring asthma, and pulmonary gamma/delta T cell function
  • 批准号:
    10300217
  • 项目类别:
  • 资助金额:
    $23.85万
  • 财政年份:
    2021
  • 负责人:
    Ian Paul Lewkowich
  • 依托单位:
Preconceptual paternal allergen exposure, offspring asthma, and pulmonary gamma/delta T cell function
  • 批准号:
    10427457
  • 项目类别:
  • 资助金额:
    $19.88万
  • 财政年份:
    2021
  • 负责人:
    Ian Paul Lewkowich
  • 依托单位:
海外基金