Asthma susceptibility due to environmental programing of innate immunity in utero

由于子宫内先天免疫的环境编程而导致哮喘易感性

基本信息

批准号：
8991512
负责人：
Magdalena Maria Gorska
金额：
$ 39.63万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8991512
关键词：
5 year old Address Adoptive Transfer Adult Age-Years Air Pollution Allergens Antibodies Antiviral Response Aromatic Polycyclic Hydrocarbons Aryl Hydrocarbon Receptor Asthma Benzo(a)pyrene Biological Preservation Cells Child DNA Adducts Data Development Diesel Exhaust Disease Environmental Exposure Epidemiologic Studies Epidemiology Exposure to Female Fostering Frequencies Gene Expression Generations Genetic Genetic Transcription Genotype Goals Health Human Immunity Immunization In Vitro Incidence Inflammation Interleukin-13 Interleukin-17 Interleukin-5 Knowledge Life Link Lung Maternal Exposure Maternal-Fetal Transmission Measures Mediating Messenger RNA Modeling Molecular Mus Mutation NK Cell Activation Natural Immunity Natural Killer Cells Organ Ovalbumin Perinatal Exposure Phenotype Predisposition Process Production Proliferating Proteins Regimen Reporting Risk Risk Factors Role Surrogate Mothers System T-Lymphocyte Transcript Up-Regulation Wheezing adaptive immunity aryl hydrocarbon receptor ligand asthma prevention asthmatic base cytokine cytotoxic disorder control early childhood early onset in utero indexing knock-down meetings mouse model offspring particle particle exposure peripheral blood postnatal pregnant prenatal prenatal environmental exposure prenatal exposure prevent programs pup research study response tumor

项目摘要

DESCRIPTION (provided by applicant): Prenatal environmental exposures are increasingly recognized as important risk factors for asthma. Critical exposures include urban air pollution and its component - diesel exhaust. The mechanisms are poorly characterized. This project seeks to address this gap in knowledge. To build a framework for mechanistic studies we have developed a mouse model. In this model, repeated exposure of pregnant mice to diesel exhaust particles (DEP) renders their offspring hypersensitive to the postnatal allergen - ovalbumin (OVA). These offspring develop asthma when subjected to suboptimal OVA sensitization and challenge. In contrast, pups born to unexposed dams do not develop asthma upon suboptimal OVA exposure. Our preliminary data indicate that asthma in this model is mediated by NK cells that produce IL-5, IL-13 and IL-17. Depletion of these cells using specific antibodies prevents asthma. We also show that IL-5/IL-13/IL-17+ NK cells are increased in human asthma. In addition to IL-5, IL-13 and IL-17 production, the pathogenic mouse NK cells are characterized by increased expression of the aryl hydrocarbon receptor (AhR) signature transcripts (AhRR, Cyp1a1 and Cyp1b1). AhR is a transcriptional factor that is known to respond to organic compounds of DEP, namely, polycyclic aromatic hydrocarbons (PAH). AhR is also known to regulate the IL-17 gene transcription. Some reports suggest the positive role of AhR in IL-5 and IL-13 production. Thus, AhR provides a molecular link between maternal exposure to DEP and cytokine production in offspring NK cells. Based on these data, our overarching hypothesis is that in utero exposure to diesel exhaust promotes asthma susceptibility through AhR-dependent priming of NK cells. We propose following specific aims: 1) Examine the importance of NK cells in asthma susceptibility induced via prenatal exposure to DEP; 2) Study the role of the aryl hydrocarbon receptor in NK cell activation and maternal-fetal transmission of asthma risk; 3) Examine the persistence of the pathogenic DEP effect through the life of first and subsequent generations; 4) Examine the relevance of IL- 5/IL-13/IL-17+ NK cells and AhR/AhRR/Cyp1b1+ NK cells in human asthma. To meet these goals we will use NK cell-deficient mice, mice without adaptive immunity and mice with NK cell-specific deletion of AhR. We will also perform transfers of NK cells from prenatally exposed offspring to unexposed mice. To study preservation of asthma susceptibility throughout the offspring life we will use cross-fostering and delayed allergen exposure approaches. To study transgenerational effects of DEP exposure, we will examine asthma susceptibility in F2 and F3 offspring. To determine human relevance we will measure IL-5/IL-13/IL-17+ NK cells and AhR/AhRR/Cyp1b1+ NK cells in young children and adults with asthma. We will correlate NK cell results with amounts of PAH-DNA adducts (a measure of environmental exposure). Using an in vitro culture system we will determine whether DEP can skew non-polarized NK cells from non-allergic non-asthmatic donors into IL-5/IL- 13/IL-17-producing cells. We will then study the role of AhR in this process using a knockdown approach.

描述（由申请人提供）：越来越多的人认识到产前环境暴露是哮喘的重要危险因素。关键暴露包括城市空气污染及其组成部分——柴油机尾气。这些机制的特征很少。该项目旨在解决这一知识差距。为了构建机制研究框架，我们开发了小鼠模型。在该模型中，怀孕小鼠反复暴露于柴油机尾气颗粒（DEP）会使它们的后代对产后过敏原 - 卵清蛋白（OVA）过敏。这些后代在受到次优的 OVA 致敏和攻击时会出现哮喘。相比之下，未接触过OVA的母鼠所生的幼崽在OVA接触次优时不会患上哮喘。我们的初步数据表明，该模型中的哮喘是由产生 IL-5、IL-13 和 IL-17 的 NK 细胞介导的。使用特异性抗体消除这些细胞可以预防哮喘。我们还表明，IL-5/IL-13/IL-17+ NK 细胞在人类哮喘中增加。除了产生 IL-5、IL-13 和 IL-17 之外，致病性小鼠 NK 细胞的特征还包括芳烃受体 (AhR) 特征转录本（AhRR、Cyp1a1 和 Cyp1b1）表达增加。 AhR 是一种转录因子，已知可响应 DEP 的有机化合物，即多环芳烃 (PAH)。 AhR 还可以调节 IL-17 基因转录。一些报告表明 AhR 在 IL-5 和 IL-13 产生中发挥积极作用。因此，AhR 提供了母体 DEP 暴露与后代 NK 细胞细胞因子产生之间的分子联系。基于这些数据，我们的总体假设是，在子宫内暴露于柴油废气会通过 AhR 依赖性 NK 细胞启动促进哮喘易感性。我们提出以下具体目标： 1) 研究 NK 细胞在产前暴露于 DEP 诱发的哮喘易感性中的重要性； 2）研究芳烃受体在NK细胞激活和哮喘风险母胎传播中的作用； 3) 检查致病性 DEP 效应在第一代和后代生命中的持续性； 4) 检查IL-5/IL-13/IL-17+ NK细胞和AhR/AhRR/Cyp1b1+ NK细胞在人类哮喘中的相关性。为了实现这些目标，我们将使用 NK 细胞缺陷型小鼠、没有适应性免疫的小鼠以及 NK 细胞特异性删除 AhR 的小鼠。我们还将将 NK 细胞从产前暴露的后代转移到未暴露的小鼠中。为了研究在整个后代生命中哮喘易感性的保持，我们将使用交叉培养和延迟过敏原暴露的方法。为了研究 DEP 暴露的跨代影响，我们将检查 F2 和 F3 后代的哮喘易感性。为了确定人类相关性，我们将测量患有哮喘的幼儿和成人中的 IL-5/IL-13/IL-17+ NK 细胞和 AhR/AhRR/Cyp1b1+ NK 细胞。我们将 NK 细胞结果与 PAH-DNA 加合物的量（环境暴露的衡量标准）相关联。使用体外培养系统，我们将确定 DEP 是否可以将来自非过敏性非哮喘供体的非极化 NK 细胞偏转为产生 IL-5/IL-13/IL-17 的细胞。然后我们将使用击倒方法研究 AhR 在此过程中的作用。