In animals and humans, offspring of allergic mothers have increased responsiveness to allergen. The maternal mediators of allergic mothers that increase allergen responsiveness in the offspring are not known. We demonstrated that the fetal liver and offspring of allergic mice have increased numbers of distinct DC subsets. Transfer of splenic dendritic cells (DCs) from neonates of allergic mothers to recipient neonates from non-allergic mothers transfers allergic responsiveness to the recipient neonates. We propose the NOVEL CONCEPT that immunoregulatory lipids in allergic mothers are transported to the offspring and that altered levels of these lipids in the offspring of allergic mothers mediate enhancement of offspring responsiveness to allergens. The following is the rationale for this novel concept: During allergic inflammation in humans and mice, lipid metabolites are altered. Maternal lipids can then across the placenta to the fetus or are in the mother’s milk during nursing. Lipid metabolites regulate DC differentiation and function, and DCs mediate initiation of allergic disease. In addition, because we demonstrated that maternal supplementation with α-tocopherol (α-T) reduces or γ-tocopherol (γ-T) elevates allergic inflammation in offspring, we propose that early in life, consumption of α-T and γ-T modulate endogenous lipid metabolites in allergic mothers that then regulate the development of offspring DC subsets that are critical for allergies in offspring. Consistent with our novel concept, our preliminary data demonstrate an increase in pro-inflammatory lipids and a decrease an anti-inflammatory lipids in the plasma and placentas of allergic mothers on mouse gestational day 18 (GD18). The decrease in anti-inflammatory lipid metabolites was blocked by maternal diet supplementation α-T. Thus, our central HYPOTHESIS is that maternal lipid metabolites elevate numbers of DCs in the fetus and neonate and that α-T reduces and γ-T elevates lipid metabolites that regulate 1) allergic responses and 2) DC subsets during the initiation of allergic lung responses. Aim 1. Test the hypothesis that, in allergic mothers, there are changes in pro-inflammatory lipid metabolites and anti-inflammatory lipid metabolites that can be transferred across the placenta to the fetus and in the milk to neonates. We will also determine whether the exogenous supplementation with α-T inhibits and γ-T elevates the generation of the endogenous lipid metabolites. Aim 2. Test the hypothesis that altered pro-inflammatory and anti-inflammatory lipid metabolites in allergic mothers regulate offspring development of DCs and allergic inflammation. It will also be determined whether human cord blood plasma lipid metabolites associate with infant atopy, DC numbers and DC function. Aim 3. Test the hypothesis that the lipid metabolites, which are altered in allergic mothers, regulate DCs in vitro. Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms of maternal lipid regulation of offspring DCs during development of allergies and 2) the design of future clinical studies. Furthermore, this may lead to novel interventions that significantly impact risk for allergic disease.
|Effective start/end date||5/1/17 → 8/31/18|
- National Institute of Allergy and Infectious Diseases (5U01AI131337-02 REVISED)
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