Epidemiology of Regulatory T Cells in Pregnancy and Childhood Atopic Diseases

描述（由申请人提供）：儿童过敏性疾病是一种日益流行的流行病，与相当高的发病率和死亡率相关。到目前为止，大多数研究都集中在产后暴露，这可能部分导致儿童过敏性疾病。与出生顺序有关的不明原因的发现和最近关于怀孕免疫的发现最近也将子宫内编程（产前暴露）推到了因果关系研究的前沿。30%的儿童过敏性疾病病例归因于孩子的出生顺序。但是，潜在的机制不能用卫生假说来解释，因为很少有证据表明感染率与出生顺序共变。过敏状态的特征是T-辅助性1/T-辅助性2比值（Th1/Th2比值）偏向于Th2细胞细胞因子优势，而Th1在过敏反应中的作用尚未明确。怀孕也被认为是Th2主导的过程。因此，怀孕可能是儿童过敏性疾病因果网络的关键组成部分。初步数据表明，抑制小鼠和人类对胎儿同种异体反应的T调节细胞（Tregs）在成功怀孕期间增加，并在产后减少，但仍高于孕前水平。最近的研究表明Tregs可以控制Th1和Th2的反应。虽然从母体到胎儿的耐受性转移模式尚未确定，但这可以解释出生顺序对随后过敏风险的影响。因此，问题是：怀孕期间母体Tregs在儿童过敏性疾病风险中的作用是什么？作为美国国立卫生研究院资助的一项正在进行的研究的一部分，一组孕妇被招募到亨利福特健康系统对她们的孩子进行纵向研究，以研究早期生活暴露在儿童过敏性疾病发展中的作用（产后规划）。使用正在进行的队列研究中的180对母子，将研究以下具体目标，以详细说明产前程序设计在儿童过敏性疾病中的作用：测定怀孕期间母体treg （CD4+CD25+CTLA4+和CD4+CD25+FOXP3+细胞计数和百分比）与分娩时（脐带）、6个月和12个月时孩子血液中的treg之间的关系；婴儿出生时（脐带）、6个月和12个月时血液中的IgE；孕妇妊娠期间的IgE水平；2. 量化从怀孕（妊娠中期）到产后（产后1、6和12个月）期间女性体内Tregs的变化；和3。确定妊娠史（先前妊娠间隔和分娩结局）与孕妇妊娠期间和产后1、6和12个月Tregs之间的关系；以及孩子出生时（脐带血）、6个月和12个月时的treg。

DESCRIPTION (provided by applicant): Childhood allergic diseases are a growing epidemic and are associated with considerable morbidity and mortality. Until now, most research has focused on postpartum exposures that may in part cause childhood allergic diseases. Unexplained findings related to birth order and recent findings on immunity in pregnancy have recently also pushed in utero programming (prenatal exposures) to the forefront in studies of causation. Thirty percent of cases of childhood allergic diseases have been attributed to a child's birth order. But, the underlying mechanism cannot be explained by the hygiene hypothesis, because there is little evidence of covariation of infection rates with birth order. Allergic status has been characterized by the T-helper1/T- helper2 ratio (Th1/Th2 ratio) skewed toward a Th2 cell-cytokine predominance, with the role of Th1 in the allergic response not yet defined. Pregnancy has also been assumed to be a Th2 dominant process. Thus pregnancy is likely a critical component in the causal web of childhood allergic diseases. Preliminary data indicate that T regulatory cells (Tregs), which suppress allogenic responses against the fetus in mice and humans, increase in successful pregnancy and decrease, but remain above prepregnancy levels, during the postpartum. Recent research has indicated that Tregs can control both Th1 and Th2 responses. Although a mode of tolerance transference from mother to fetus has not yet been identified, this could explain the effect of birth order on subsequent allergic risk that has been seen. Hence the question: what is the role of maternal Tregs during pregnancy in the risk of childhood allergic diseases? As part of an ongoing NIH- funded study, a cohort of pregnant women is being recruited for longitudinal study of their children at Henry Ford Health System to study the role of early life exposures in the development of childhood allergic disease (postnatal programming). Using a subset of 180 mother-child pairs from this ongoing cohort study, the following specific aims will be studied to detail the role of prenatal programming in childhood allergic disease: 1. Determine the relationships between maternal Tregs (CD4+CD25+CTLA4+ and CD4+CD25+FOXP3+ cells - counts and percentages) during pregnancy and: Tregs in their child's blood at delivery (cord), and 6 and 12 months; IgE in their child's blood at delivery (cord), and 6 and 12 months; and maternal IgE during pregnancy; 2. Quantify the within-woman change in Tregs from pregnancy (second trimester) throughout the postpartum period (1, 6 and 12 months postpartum); and 3. Determine the relationship between pregnancy history (prior pregnancy intervals and birth outcomes) and: maternal Tregs during pregnancy and 1, 6 and 12 months postpartum; and the child's Tregs at delivery (cord blood) and 6 and 12 months.