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

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 迁徙的人口表明，当地环境，如饮食，在发展 哮喘。在过去的40年里，一个环境变化是d-γ-生育酚(γ-T)在 节食。在我们对成年小鼠的机制研究中，γ-T增加5倍会增加嗜酸性粒细胞过敏性肺 炎症(175%)和呼吸道反应，而另一种生育酚亚型α-T增加5倍， 阻止嗜酸性过敏反应(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，我们证明了γ-T是一种激动剂，而α-T是一种蛋白质拮抗剂。 蛋白激酶C(PKC)。此外，在我们对成年人的研究中，血浆α-T水平高出5倍 随着更好的肺活量测定和γ-T增加5倍与较低的肺活量测定相关(减少10%到17% FEV1)；这发生在21岁时，这表明在生命早期，生育酚亚型可能调节发育 以及肺部对环境暴露的反应。我们提出了一个新的概念，在生命的早期，α-T和γ-T 调节树突状细胞(DC)的发育和过敏性疾病。与我们的新概念一致，我们 结果表明，补充γ-T可使妊娠变态反应小鼠的仔鼠α-T水平升高，而能降低仔鼠的体重 变态反应和肺CD11b+CD11c+DC亚群在变态反应启动中的关键作用 发炎。此外，α-T在幼鼠生命早期的抑制作用持续存在。在体外，γ-T 增加和α-T减少骨髓来源的DC的数量，表明至少有调节功能 生育酚对DC分化的影响。α-T和γ-T调控DC发育的机制 过敏反应尚不清楚。我们的长期目标是确定α-T和γ-T的调节机制 树突状细胞的发展和过敏反应。作为迈向我们长期目标的一步，我们的中央 假说是在生命早期，α-T减少而γ-T升高调节过敏反应的介质 (2)CD11b+CD11c+DC在肺变态反应启动过程中的发育和功能。我们会 用以下目标测试我们的中心假设：目标1.测试母体α-T降低和 γ-T上调子代细胞因子和生长因子，调节DC和T细胞的发育 生命早期的过敏原。目的2.验证α-T抑制和γ-T上调DC蛋白激酶C活性的假说 T细胞DC活化过程中CD11b+CD11c+DC分化活化和T细胞PKC活性的变化。 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 过敏发展过程中树突状细胞α-T和γ-T调节的研究2)α-T的临床研究设计 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。

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.