Regulatory T Cells in Gestation and Childhood Allergic Disease

描述(由申请人提供)：流行病学和结果研究(K01)的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，从生殖流行病学过渡到儿童过敏性疾病(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领域的独立研究员所需的技能。冠心病是一种日益流行的疾病，与死亡率和相当大的发病率有关。30%的病例被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，因为几乎没有证据表明感染率与出生顺序之间存在协变性。过敏状态的特征是T辅助细胞1/T辅助2比率(Th1/Th2比率)倾向于Th2细胞-细胞因子占优势，Th1在过敏反应中的作用尚未确定。妊娠被认为是Th2占优势的过程。因此，怀孕很可能是冠心病因果网络中的一个关键组成部分。T调节细胞(Tregs)在小鼠和人类中抑制针对胎儿的同种异体反应，在成功怀孕时增加，在产后减少，但仍高于怀孕前的水平。研究表明，Tregs可以同时控制Th1和Th2的反应。虽然母亲对胎儿的耐受性转移模式尚未确定，但这可以解释观察到的出生顺序与随后的冠心病风险之间的关联。由此产生的问题是：怀孕期间母体妊娠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，底特律地区正在招募一名出生队列进行纵向研究，以研究CAD发展过程中早期生命暴露的情况。使用来自该队列的225对母子对的子集，我们将研究以下假设(树：CD4CD25FOXP3和CD4CD25CTLA4)。我们的假设是：1)更多的先前活产和更短的怀孕间隔将预测：a.怀孕期间以及产后1、6和12个月的孕妇Tregs较高；b.孕妇产前IgE较低；以及2)孕期较高的Tregs预测：a.分娩时(脐带)、6、12个月和2岁时孩子血液中的Tregs较高；b.分娩时(脐带)、6、12个月和2岁时孩子血液中的IgE较低；c.他们的孩子在2岁时对常见的空气过敏原和食物过敏原皮肤点刺试验呈阳性的风险降低。

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.