Tocopherol regulation of the development of responsiveness to allergen early in life

生育酚对生命早期过敏原反应性发展的调节

• 批准号: 9380183
• 负责人: JOAN M COOK-MILLS
• 金额: $ 55.9万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-23 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380183
• 关键词: 21 year old; Address; Adult; Agonist; Allergens; Allergic; Allergic Disease; Allergic inflammation; Asthma; Binding; Bone Marrow; Cell Differentiation process; Child; Clinical Research; Complex; Country; Dendritic Cells; Dendritic cell activation; Development; Diet; Disease; Environment; Environmental Exposure; Extrinsic asthma; Female; Fetal Liver; Future; Future Generations; Genetic; Goals; Growth Factor; Human; Hypersensitivity; ITGAM gene; ITGAX gene; IgE; In Vitro; Infant formula; Intervention; Lead; Life; Lung; Lung Inflammation; Mediator of activation protein; Mothers; Mus; PRKCA gene; Plasma; Population; Prevalence; Protein Isoforms; Protein Kinase C; Pulmonary Function Test/Forced Expiratory Volume 1; Recombinant Proteins; Recombinants; Recruitment Activity; Regulation; Reporting; Respiratory physiology; Risk; Role; Signal Transduction; Soybean Oil; Spirometry; Structure; Supplementation; T cell response; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Tissues; Tocopherols; Translating; Vitamin E; Wheezing; World Health Organization; allergic response; alpha Tocopherol; cohort; cytokine; design; environmental change; eosinophil; gamma-Tocopherol; in utero; in vivo; methyl group; mouse model; neonate; novel; offspring; pregnant; protein activation; pup; response; therapy design; transmission process

The marked rise in rates of asthma over a few decades and the differences in rates among countries and in migrating populations suggest an important role of the local environment, such as diet, in development of asthma. One environmental change over the past 40 years has been an increase in d-γ-tocopherol (γ-T) in the diet. In our mechanistic studies in adult mice, a 5-fold increase in γ-T elevates eosinophilic allergic lung inflammation (175%) and airway responses whereas a 5-fold increase in another tocopherol isoform, α-T, blocks eosinophilic allergic responses (65% decrease). In mechanistic studies of signals for eosinophil recruitment in allergic asthma, we demonstrated that γ-T is an agonist and α-T is an antagonist of protein kinase C (PKC). Moreover in our studies with adult humans, a 5-fold higher plasma α-T level associates with better spirometry and a 5-fold increase in γ-T associates with lower spirometry (10 to 17% decrease in FEV1); this occurred by age 21, suggesting that early in life, tocopherol isoforms may regulate development and lung responses to environmental exposures. We propose a novel concept that early in life, α-T and γ-T regulate the development of dendritic cells (DCs) and allergic disease. Consistent with our novel concept, we demonstrated that supplementation of allergic pregnant mice with γ-T increased and α-T decreased pup allergic responses and subsets of lung CD11b+CD11c+ subsets of DCs that are critical to initiation of allergic inflammation. In addition, the inhibitory effect of α-T early in life was sustained in the pups. In vitro, γ-T increased and α-T decreased numbers of bone-marrow-derived DCs, suggesting at least a regulatory function of tocopherols on differentiation of DCs. Mechanisms for α-T and γ-T regulation of the development of DCs and allergic responses are not known. Our long term goal is to identify mechanisms for α-T and γ-T regulation of the development of DCs and allergic responses. As a step towards our long-term goal, our central HYPOTHESIS is that early in life, α-T reduces and γ-T elevates mediators that regulate 1) allergic responses and 2) CD11b+CD11c+ DC development and function during the initiation of allergic lung responses. We will test our central hypothesis with the following aims: Aim 1. Test the hypothesis that maternal α-T reduces and γ-T elevates offspring cytokines and growth factors that regulate development of DC and T cell responses to allergen early in life. Aim 2. Test the hypothesis that α-T inhibits and γ-T elevates DC PKC activity during CD11b+CD11c+ DC differentiation and activation and T cell PKC activity during DC activation of T cells. Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms of α-T and γ-T regulation of DCs during development of allergies and 2) the design of clinical studies with α-T and γ-T. Furthermore, these studies will provide a basis for design of interventions that significantly impact risk for allergic disease.

几十年来哮喘发病率显着上升，不同国家和地区之间的发病率存在差异 迁徙人口表明当地环境（例如饮食）在发展中发挥着重要作用 过去 40 年来的一项环境变化是体内 d-γ-生育酚 (γ-T) 的增加。 在我们对成年小鼠的机制研究中，γ-T 增加 5 倍会导致肺嗜酸性粒细胞过敏。 炎症 (175%) 和气道反应，而另一种生育酚异构体 α-T 则增加 5 倍， 阻断嗜酸性粒细胞过敏反应（减少 65%）。 在过敏性哮喘中，我们证明了 γ-T 是蛋白质的激动剂，α-T 是蛋白质的拮抗剂 此外，在我们对成年人的研究中，血浆 α-T 水平升高 5 倍。 肺活量测定结果更好，γ-T 增加 5 倍，肺活量测定结果降低（10% 至 17% 减少） FEV1)；这发生在 21 岁时，表明生育酚亚型可能在生命早期调节发育 我们提出了一个新概念，即在生命早期，α-T 和 γ-T。 调节树突状细胞（DC）和过敏性疾病的发展与我们的新概念一致，我们。 过敏怀孕小鼠的补充表明，幼鼠的 γ-T 增加，α-T 减少 过敏反应和肺 CD11b+CD11c+ 亚群 DC 亚群对过敏反应的发生至关重要 此外，在体外，α-T 的抑制作用在幼崽中得以持续。 骨髓来源的 DC 数量增加且 α-T 数量减少，表明至少具有调节功能 生育酚对 DC 分化的影响 α-T 和 γ-T 调节 DC 发育的机制。 我们的长期目标是确定 α-T 和 γ-T 调节机制。 作为实现我们长期目标的一步，我们的核心是 DC 的发展和过敏反应。 假设在生命早期，α-T 会减少调节介质，而 γ-T 则会升高介质，从而调节 1) 过敏反应 2) CD11b+CD11c+ DC 在过敏性肺部反应启动期间的发育和功能。 测试我们的中心假设，目的如下： 目标 1. 测试母体 α-T 降低和 γ-T 升高后代细胞因子和生长因子，调节 DC 和 T 细胞对 目标 2. 检验 α-T 抑制和 γ-T 升高 DC PKC 活性的假设。 CD11b+CD11c+ DC 分化和激活以及 DC 激活 T 细胞期间的 T 细胞 PKC 活性。 成功完成这些研究将对 1）我们对机制的理解产生重大影响 过敏发展过程中 α-T 和 γ-T 对 DC 的调节以及 2) α-T 临床研究的设计 此外，这些研究将为设计显着影响风险的干预措施提供基础。 用于过敏性疾病。