Regulatory T Cells in Gestation and Childhood Allergic Disease

描述（由申请人提供）：获得流行病学与成果研究（K01）指导研究科学家发展奖，将使我在一个成功的CAD流行病学研究小组的指导下，从生殖流行病学转向儿童过敏性疾病（CAD）流行病学研究。通过这个拟议的研究和培训计划，我将发展成为CAD领域独立研究人员所需的技能。CAD是一种日益流行的流行病，与死亡率和相当高的发病率有关。30%的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-helper1/T-helper2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。怀孕被认为是Th2主导的过程。因此，怀孕可能是CAD因果网络的关键组成部分。T调节细胞（Tregs）抑制小鼠和人类对胎儿的同种异体反应，在成功怀孕期间增加和减少，但在产后仍高于孕前水平。研究表明Tregs可以同时控制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，但这可以解释已观察到的出生顺序与随后的CAD风险之间的关联。因此，问题是：怀孕期间母体Tregs在冠心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，正在底特律地区招募一个出生队列进行纵向研究，以研究CAD发展的早期生活暴露。使用来自该队列的225对母子的子集，我们将研究以下假设（Tregs: CD4+CD25+FOXP3+和CD4+CD25+CTLA4+）。我们的假设是：1)更多的活产和更短的妊娠间隔将预测：a.怀孕期间和产后1、6和12个月的产妇Tregs较高；b.孕妇产前IgE较低；a.分娩时（脐带血）、6个月、12个月和2岁时孩子血液中Tregs升高；b.婴儿出生时（脐带）、6个月、12个月和2岁时血液中IgE较低；c.降低孩子在2岁时皮肤点刺试验中常见空气过敏原和食物过敏原阳性的风险。

DESCRIPTION (provided by applicant): This Mentored Research Scientist Development Award in Epidemiology and Outcomes Research (K01) will allow me to transition from reproductive epidemiology to childhood allergic disease (CAD) epidemiology research under the guidance of a successful CAD epidemiology research group. Through this proposed research and training program, I will develop the skills needed to become an independent researcher in the field of CAD. CAD are a growing epidemic and are associated with mortality and considerable morbidity. Thirty percent of cases have been attributed to the children'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 is assumed to be a Th2 dominant process. Thus pregnancy is likely a critical component in the causal web of CAD. T regulatory cells (Tregs), which suppress allogenic responses against the fetus in mice and humans, increase in successful pregnancy and decrease, but remain above pre-pregnancy levels, during the postpartum. 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 observed association between birth order and subsequent CAD risk. Hence the question: what is the role of maternal Tregs during pregnancy in the risk of CAD? As part of an ongoing NIH-funded study, a birth cohort is being recruited for longitudinal study in the Detroit area to study early life exposures in the development of CAD. Using a subset of 225 mother-child pairs from this cohort, we will study the following hypotheses (Tregs: CD4+CD25+FOXP3+ and CD4+CD25+CTLA4+). Our hypotheses are: 1) More prior live births and shorter pregnancy intervals will be predictive of: a. Higher maternal Tregs during pregnancy and at 1, 6 and 12 months postpartum; b. Lower maternal prenatal IgE; and 2) Higher maternal Tregs during pregnancy are predictive of: a. Higher Tregs in their child's blood at delivery (cord), 6 and 12 months and 2 years; b. Lower IgE in their child's blood at delivery (cord), 6 and 12 months and 2 years; c. Reduced risk of their child having a positive skin prick test for common aeroallergens and food allergens at age 2 years.