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的显著上升以及国家和地区之间的发病率差异， 迁移人口表明当地环境的重要作用，如饮食，在发展中， 哮喘在过去的40年中，一个环境变化是d-γ-生育酚（γ-T）的增加， 饮食.在我们对成年小鼠进行的机制研究中，γ-T增加5倍会使嗜酸性粒细胞过敏性肺 炎症（175%）和气道反应，而另一种生育酚亚型α-T， 阻断嗜酸性粒细胞过敏反应（减少65%）。在嗜酸性粒细胞信号的机制研究中， 在过敏性哮喘中，我们证明γ-T是蛋白质的激动剂，α-T是蛋白质的拮抗剂 激酶C β（PKC β）。此外，在我们对成年人的研究中，血浆α-T水平升高5倍与 更好的肺功能测定和γ-T增加5倍与较低的肺功能测定相关（ FEV 1）;这发生在21岁，表明在生命早期，生育酚异构体可能调节发育 和肺对环境暴露的反应。我们提出了一个新的概念，即在生命早期，α-T和γ-T 调节树突状细胞（DCs）的发育和过敏性疾病。根据我们的新概念，我们 结果表明，补充γ-T可增加过敏性妊娠小鼠的仔鼠数，而补充α-T可减少仔鼠数。 过敏反应和肺CD 11b + CD 11 c + DC亚群的亚群，这些亚群对过敏反应的启动至关重要。 炎症此外，α-T在生命早期的抑制作用在幼仔中持续存在。体外，γ-T 增加和α-T减少骨髓来源的DC数量，表明至少有调节功能 对DC分化的影响。α-T和γ-T调节树突状细胞发育的机制 和过敏反应尚不清楚。我们的长期目标是确定α-T和γ-T调节的机制 树突状细胞和过敏反应的发展。为了实现我们的长期目标，我们的中央 假设在生命早期，α-T减少而γ-T升高调节1）过敏反应的介质 （2）CD 11b + CD 11 c + DC在过敏性肺反应启动过程中的发育和功能。我们将 测试我们的中心假设与以下目标：目标1。检验母体α-T降低和 γ-T升高后代细胞因子和生长因子，调节DC的发育和T细胞对 过敏原在生命早期目标二。验证α-T抑制和γ-T升高DC PKC活性的假设， CD 11b + CD 11 c + DC的分化和活化以及DC活化过程中T细胞的PKC活性。 这些研究的成功完成将对1）我们对机制的理解产生重大影响 α-T和γ-T调节DCs在变态反应发展过程中的作用; 2）α-T临床研究的设计 和γ-T。此外，这些研究将为设计显著影响风险的干预措施提供基础。 治疗过敏性疾病