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领域的指导研究科学家发展奖 (K01) 将使我能够在成功的 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，我将培养成为 CAD 领域的独立研究员所需的技能。 CAD 是一种日益严重的流行病，与死亡率和发病率相当高有关。百分之三十的病例归因于孩子的出生顺序。但是，根本机制无法用卫生假说来解释，因为几乎没有证据表明感染率与出生顺序存在共变。过敏状态的特征是 T 辅助细胞 1/T 辅助细胞 2 比率（Th1/Th2 比率）偏向 Th2 细胞-细胞因子优势，而 Th1 在过敏反应中的作用尚未确定。妊娠被认为是 Th2 主导的过程。因此，妊娠可能是 CAD 因果网络中的一个关键组成部分。 T 调节细胞（Treg）可抑制小鼠和人类对胎儿的同种异体反应，在成功怀孕时会增加，在产后会减少，但仍高于怀孕前的水平。研究表明 Tregs 可以控制 Th1 和 Th2 反应。尽管尚未确定从母亲到胎儿的耐受性转移模式，但这可以解释所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：妊娠期间母体 Tregs 在 CAD 风险中发挥什么作用？作为 NIH 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组出生队列进行纵向研究，以研究 CAD 发展中的早期暴露情况。使用该队列中 225 对母子的子集，我们将研究以下假设（Treg：CD4 CD25 FOXP3 和 CD4 CD25 CTLA4）。我们的假设是： 1) 更多的先前活产和更短的怀孕间隔将预示：怀孕期间以及产后 1、6 和 12 个月时母体 Tregs 较高； b.降低母亲产前 IgE； 2) 怀孕期间母体 Tregs 水平较高可预测：孩子在分娩（脐带）、6 个月、12 个月和 2 岁时血液中的 Tregs 含量较高； b.孩子分娩时（脐带）、6 个月、12 个月和 2 岁时血液中的 IgE 较低； c.降低孩子 2 岁时对常见空气过敏原和食物过敏原进行皮肤点刺测试呈阳性的风险。

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.