Vitamin D supplementation in pregnancy: impact on neonatal immune phenotype

妊娠期补充维生素 D：对新生儿免疫表型的影响

• 批准号: 8029495
• 负责人: William W Cruikshank
• 金额: $ 31.13万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-16 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8029495
• 关键词: 1 year old; 5 year old; 6 year old; Adrenal Cortex Hormones; Adult; Affect; Age; Allergens; Ancillary Study; Antibodies; Antigen-Presenting Cells; Asthma; Autoimmunity; Automobile Driving; Biological Assay; Biological Markers; Biology; Boston; Calcitriol; Cell Culture Techniques; Cells; Child; Childhood; Clinical; Clinical Trials; Collection; Data; Data Coordinating Center; Development; Diagnosis; Dietary intake; Dose; Environment; Environmental Risk Factor; Enzyme-Linked Immunosorbent Assay; Epidemiologic Studies; Epidemiology; Equilibrium; Event; Exposure to; Flow Cytometry; Frequencies; Funding; Goals; Grant; Health; High Prevalence; Homeostasis; Human; Hypersensitivity; Immune; Immune System Diseases; Immune system; Immunity; Immunoglobulins; Immunology; In Vitro; Incidence; Interleukin-10; Laboratories; Lead; Life; Life Style; Link; London; Lung diseases; Maintenance; Malignant Neoplasms; Measurement; Medical center; Mononuclear; Morbidity - disease rate; Mothers; NIH Program Announcements; Neonatal; Newborn Infant; Outcome; Phenotype; Population; Pregnancy; Pregnant Women; Prevalence; Principal Investigator; Process; Production; Recruitment Activity; Recurrence; Regulatory T-Lymphocyte; Request for Applications; Research; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Sampling; Scotland; Serum; Specimen; Staining method; Stains; Sunlight; Supplementation; T-Lymphocyte; Testing; Time; Umbilical Cord Blood; United States National Institutes of Health; Universities; Vitamin D; Vitamin D Deficiency; Wheezing; Woman; base; college; cytokine; functional disability; in utero; infancy; neonatal human; neonate; offspring; prevent; programs; pulmonary function; respiratory

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.

描述（由申请人提供）： 哮喘是儿童和成人发病的主要原因，全球估计有 3 亿患者。近几十年来，哮喘发病率急剧上升，大多数哮喘患者在 6 岁（1-7 岁）期间被诊断出来。这种增加与影响生命早期免疫系统的环境因素的变化有关 (8-10)。其中一个潜在因素是维生素 D，它主要通过暴露在阳光下获得。维生素 D 缺乏症在全世界范围内普遍存在 (11, 12)，与自身免疫、癌症 (12, 13) 和肺功能不良 (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，怀孕期间母亲膳食中维生素 D 的摄入量较高与 3 岁和 5 岁儿童反复喘息的风险显着降低相关 (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 名女性，旨在研究怀孕期间补充高剂量维生素 D 对后代喘息和呼吸道疾病发生率的影响（NIH 拨款号：U01HL091528，联合 PI：利通华和韦斯）。维生素 D 是免疫的重要调节剂。维生素 D 的活性形式可提高两种不同的 T 调节细胞 (Treg) 群体的频率，即分泌 IL-10 的细胞 (17) 和 Foxp3+ Treg 细胞 (18)。这些 Treg 维持呼吸环境中的免疫稳态 (19)。它们的功能障碍见于幼儿和脐带血的过敏和哮喘 (19-24)。维生素 D 可能通过增强皮质类固醇的反应性而对哮喘有进一步的益处 (25)。我们假设母体维生素 D 状态会影响新生儿的免疫力，特别是 Foxp3+Treg 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鉴定活性维生素 D、骨化三醇诱导 IL-10-Treg 与 Foxp3+Treg 的能力；抗原呈递细胞的作用；骨化三醇诱导的 Foxp3+Treg 与 IL-10-Treg 的抑制能力和特异性生物标志物。 2. 母体维生素 D 水平低是否会导致新生儿免疫发育受损以及效应 T 细胞群的调节失衡？一项经伦理批准的临床试验（NIH 批准号：U01HL091528）将提供妊娠期间接受 400IU（低）与 4400IU 维生素 D（高）补充剂的母亲的婴儿的脐带血单核细胞样本，以研究母亲维生素 D 状态如何改变免疫细胞组成，包括效应和调节性 T 细胞频率；过敏原诱导的细胞因子产生； Foxp3+Treg 与 IL-10-Treg 的诱导能力；以及对皮质类固醇诱导 IL-10 的反应。 3. 免疫学参数是否可以预测与子宫内维生素 D 状态相关的临床结果？公共健康相关性：本申请是对临床试验辅助研究申请计划公告 (RFA-HL-09-001) 的回应，旨在确定孕妇补充维生素 D 影响新生儿免疫状态的机制，以及是否这可以预测与呼吸系统健康相关的临床结果。在怀孕期间、婴儿期、儿童期和成年期补充维生素 D 是一个相对简单且可实现的临床目标，但对呼吸系统健康可能产生巨大影响。如果我们关于怀孕期间母体维生素 D 状态对新生儿（脐带血）调节性 T 细胞群影响的假设是正确的，那么这些益处将远远超出呼吸系统健康的范畴，还会对一系列其他免疫疾病产生影响，包括自身免疫性疾病。众所周知，Treg 具有功能。