Regulatory T Cells in Gestation and Childhood Allergic Disease

Henry Ford Health System, Detroit MI

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Abstract

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.