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: 7853263
• 负责人: William W Cruikshank
• 金额: $ 32.33万
• 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/7853263
• 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; public health relevance; 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）时被诊断出来。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）。一个潜在的因素是维生素D，主要通过暴露在阳光下获得。维生素D不足的高患病率在世界范围内存在（11，12），与自身免疫，癌症（12，13）和肺功能差（14）。我们在马萨诸塞州波士顿和苏格兰阿伯丁的合作者表明，怀孕期间母亲饮食中维生素D摄入量较高与3岁和5岁儿童复发性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，旨在研究妊娠期补充高剂量维生素D对后代喘息和呼吸系统疾病发生率的影响（NIH批准号：U 01 HL 091528，共同PI：Litonjua &韦斯）。维生素D是一种重要的免疫调节剂。活性形式的维生素D提高了两种不同的调节性T细胞（Treg）群体的频率，即分泌IL-10的细胞（17）和Foxp 3 + Treg细胞（18）。这些Treg维持呼吸环境中的免疫稳态（19）。他们的功能障碍见于幼儿过敏和哮喘以及脐带血（19-24）。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）。我们假设母体维生素D状况影响新生儿的免疫力，特别是Foxp 3 +Treg和IL-10-Treg细胞的频率和功能。我们将调查：1。维生素D在体外促进脐带血中功能性Foxp 3+和IL-10+调节性T细胞吗？这些研究将利用来自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Foxp 3 +Treg的能力;抗原呈递细胞的作用;骨化三醇诱导的Foxp 3 +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，以及调节效应T细胞群的不适当平衡？一项伦理上认可的临床试验（NIH资助号：U 01 HL 091528）将提供来自母亲在怀孕期间接受400 IU（低）与4400 IU维生素D（高）补充剂的婴儿的脐带血单核细胞样本，以研究母体维生素D状态如何改变免疫细胞组成，包括效应和调节T细胞频率;过敏原诱导的细胞因子产生; Foxp 3 +Treg相对于IL-10-Treg的诱导;以及对皮质类固醇诱导IL-10的反应性。3.免疫学参数能预测与子宫内维生素D状态相关的临床结局吗？公共卫生关系：本申请是对临床试验辅助研究申请项目公告（RFA-HL-09-001）的响应，旨在确定孕妇补充维生素D影响新生儿免疫状态的机制，以及这是否可预测与呼吸系统健康相关的临床结局。在怀孕期间，婴儿期，儿童期和成年期补充维生素D是一个相对简单和可实现的临床目标，对呼吸系统健康有潜在的巨大影响。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）中调节性T细胞群的影响的假设是正确的，这些益处将远远超出呼吸系统健康，并影响一系列其他免疫疾病，包括自身免疫，其中Treg已知发挥作用。