Vitamin D supplementation in pregnancy: impact on neonatal immune phenotype

描述(由申请人提供)： 哮喘是儿童和成人发病率的主要原因，全世界估计有3亿患者。近几十年来，发病率急剧上升，大多数哮喘患者在6岁(1-7岁)被诊断为哮喘。这种增加与早期生命中影响免疫系统的环境因素的变化有关(8-10岁)。一个潜在的因素是维生素D，主要是通过暴露在阳光下获得的。维生素D缺乏在世界范围内普遍存在(11，12)，与自身免疫、癌症(12，13)和肺功能低下(14)有关。我们在马萨诸塞州波士顿和苏格兰阿伯丁的合作者表明，孕妇在怀孕期间摄入较高的维生素D与3岁和5岁儿童反复喘息的风险显著降低相关(15)(16)。这些数据构成了最近资助的一项临床试验的基础，该试验涉及870名妇女，研究怀孕期间补充大剂量维生素D对子女喘息和呼吸系统疾病发生率的影响(NIH资助号：U01HL091528，联合PIs：Litonjua&Weiss)。维生素D是一种重要的免疫调节剂。维生素D的活性形式提高了两种不同的T调节细胞(Treg)的频率，IL-10分泌(17)和Foxp3 Treg细胞(18)。这些Treg在呼吸环境中维持免疫平衡(19)。他们的功能障碍表现为过敏和幼儿哮喘以及脐带血(19-24岁)。维生素D可能通过增强皮质类固醇的反应性对哮喘有进一步的益处(25)。我们假设母亲的维生素D状态影响新生儿的免疫，特别是Foxp3Treg和IL-10-Treg细胞的频率和功能。我们将研究：1.维生素D是否在体外促进脐带血中功能性Foxp3和IL-10调节性T细胞？这些研究将利用健康足月分娩的脐带血来确定活性维生素D骨化三醇诱导IL-10-Treg与Foxp3-Treg的能力；抗原提呈细胞的作用；骨化三醇诱导的Foxp3 Treg与IL-10-Treg的抑制能力和生物标志物。2.母亲体内维生素D水平低是否会导致新生儿免疫发育受损，并导致调节效应T细胞数量的不适当平衡？一项经伦理学批准的临床试验(NIH资助号：U01HL091528)将提供孕期补充维生素D 400IU(低)与4400IU(高)的母亲的婴儿脐带血单个核细胞样本，以研究母亲维生素D状态如何改变免疫细胞组成，包括效应者和调节性T细胞频率；变应原诱导的细胞因子产生；Foxp3 Treg与IL-10-Treg的诱导性；以及皮质类固醇诱导IL-10的反应性。3.免疫学参数预测临床结果是否与子宫内维生素D状态有关？公共卫生相关性：该应用程序响应临床试验辅助研究的申请程序公告(RFA-HL-09-001)，旨在确定孕妇补充维生素D影响新生儿免疫状态的机制，以及这是否可以预测与呼吸健康相关的临床结果。在孕期、婴儿期、儿童期和成年期补充维生素D代表了一个相对简单和可实现的临床目标，对呼吸健康有潜在的巨大影响。如果我们关于怀孕期间母亲维生素D状态对新生儿(脐带血)中调节性T细胞数量的影响的假设是正确的，这些好处将远远超出呼吸健康并影响一系列额外的免疫疾病，包括已知的Treg发挥作用的自身免疫。

DESCRIPTION (provided by applicant): Asthma is a leading cause of childhood and adult morbidity with an estimated 300 million sufferers worldwide. The incidence has risen dramatically in recent decades, with most asthmatics diagnosed by 6 years of age (1-7). This increase is linked to changes in environmental factors affecting the immune system in early life (8-10). One potential factor is vitamin D, acquired primarily via exposure to sunlight. A high prevalence of vitamin D insufficiency exists worldwide (11, 12), associated with autoimmunity, cancer (12, 13) and poor pulmonary function (14). Our collaborators in Boston, MA and Aberdeen, Scotland showed that higher maternal dietary intake of vitamin D during pregnancy is associated with a significantly lower risk for recurrent wheezing in 3- and 5-year old children (15) (16). These data form the basis for a recently funded clinical trial, involving 870 women, to study the effects of high dose vitamin D supplementation in pregnancy on the incidence of wheeze and respiratory disease in the offspring (NIH Grant number: U01HL091528, co-PIs: Litonjua & Weiss). Vitamin D is an important modulator of immunity. The active form of vitamin D enhances the frequency of two distinct populations of T regulatory cells (Treg), IL-10 secreting (17) and Foxp3+ Treg cells (18). These Treg maintain immune homeostasis in the respiratory environment (19). Their functional impairment is seen in allergy and asthma in young children and cord blood (19-24). Vitamin D may have further benefit in asthma by enhancing responsiveness of corticosteroids (25). We hypothesize that maternal vitamin D status influences immunity in the neonate, specifically the frequency and function of Foxp3+Treg and IL-10-Treg cells. We will investigate: 1. Does vitamin D promote functional Foxp3+ and IL-10+ regulatory T cells in cord blood in vitro? These studies will utilize cord blood from healthy, term deliveries to identify the capacity of active vitamin D, calcitriol, to induce IL-10-Treg vs. Foxp3+Treg; the role of antigen presenting cells; the suppressive capacity of and biomarkers specific to calcitriol-induced Foxp3+Treg vs. IL-10-Treg. 2. Do low maternal levels of vitamin D lead to impaired immune development in the neonate, and an inappropriate balance of regulatory to effector T cell populations? An ethically approved clinical trial (NIH Grant Number: U01HL091528) will provide cord blood mononuclear cell samples from babies of mothers receiving 400IU (low) versus 4400IU vitamin D (high) supplementation during pregnancy to study how maternal vitamin D status alters immune cell composition, including effector and regulatory T cell frequencies; allergen-induced cytokine production; the inducibility of Foxp3+Treg versus IL-10-Treg; and the responsiveness to corticosteroids for induction of IL-10. 3. Do immunological parameters predict clinical outcome related to vitamin D status in utero? PUBLIC HEALTH RELEVANCE: This application is responsive to the Request for Applications program announcement for ancillary studies in clinical trials (RFA-HL-09-001) and aims to identify mechanisms whereby vitamin D supplementation of pregnant women influences immune status in the neonate and whether this predicts clinical outcome related to respiratory health. Vitamin D supplementation during pregnancy, in infancy, childhood and adult life represents a comparatively simple and achievable clinical goal with potentially huge impact on respiratory health. If our hypotheses regarding the impact of maternal vitamin D status during pregnancy on regulatory T cell populations in the newborn (cord blood) are correct these benefits will extend well beyond respiratory health and impact on a range of additional immune disorders, including autoimmunity, in which Treg are known to function.