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Grant Abstract: Tocopherol regulation of the development of responsiveness to allergen early in life

Grant Number: 5R01AI127695-04
PI Name: Cook-Mills
Project Title: Tocopherol regulation of the development of responsiveness to allergen early in life

Abstract: In the parent grant (R01AI127695), we will determine mechanisms of dietary tocopherol isoform regulation of allergic asthma in mice and humans. This administrative supplement enhances the parent award by analyzing mechanisms of dietary tocopherol isoform regulation of the development of another allergic disease, food allergy. Food allergy can be life-threatening, has no cure, and has had a marked recent increase in prevalence. Approaches to reduce the development of food allergy in children are needed. One of the environmental changes over the past 40 years has been an increase in d-?-tocopherol (?-T) in the diet and an increase in ?-T in infant formulas because formulas contain soybean oil that is rich in ?-T. The two most abundant natural forms of tocopherols are d-a-tocopherol (a-T) and ?-T in the diet and tissues. In our mechanistic studies of signals for eosinophil recruitment in allergic asthma, we demonstrated that ?-T is an agonist and a-T is an antagonist of recombinant protein kinase Ca (PKCa), that a-T and ?-T bind to a regulatory domain of PKCa, and that a-T and ?-T have opposing function in preclinical models of asthma and in associations with human lung function. It is not known whether a-T and ?-T regulates food allergy. Our new preliminary data demonstrates that tocopherol isoforms regulate food allergy outcomes. Briefly, early childhood plasma a-T associates with lower food allergen-specific IgE in children and in mice, a-T supplementation during pregnancy/nursing blocks development of food allergy in offspring. Interventions are critical to limit the development of food allergy early in life. We propose a novel concept that early in life, a-T and ?-T regulate the development of allergic disease (asthma in the parent grant and food allergy in this administrative supplement). Our long term goal is to identify mechanisms for a-T and ?-T regulation of development of DCs and allergic responses. As a step towards our long-term goal, our central HYPOTHESIS for this administrative supplement is that early in life, a-T reduces and ?-T elevates mediators that regulate 1) development of food allergy and 2) CD11b+CD11c+ DC development and function during the initiation of food allergy. We will test this with the following aims: Aim 1. Test the hypothesis that maternal a-T reduces and ?-T elevates offspring cytokines and growth factors that regulate development of DC and T cell responses to food allergens early in life. Aim 2. Test the hypothesis that a-T or ?-T treatment of bone marrow differentiation of DCs in vitro is sufficient to regulate DC FUNCTION for sensitization and induction of food allergy and T cell proliferation in neonates, a Th2 skewed environment. Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms of a-T and ?-T regulation of DCs during development of food allergy and 2) the design of future clinical studies with a-T and ?-T. Furthermore, this may lead to interventions that significantly impact risk for food allergy.

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