# Tocopherol regulation of the development of responsiveness to allergen early in life

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2020 · $437,672

## Abstract

The marked rise in rates of asthma over a few decades and the differences in rates among countries and in
migrating populations suggest an important role of the local environment, such as diet, in development of
asthma. One environmental change over the past 40 years has been an increase in d-γ-tocopherol (γ-T) in the
diet. In our mechanistic studies in adult mice, a 5-fold increase in γ-T elevates eosinophilic allergic lung
inflammation (175%) and airway responses whereas a 5-fold increase in another tocopherol isoform, α-T,
blocks eosinophilic allergic responses (65% decrease). In mechanistic studies of signals for eosinophil
recruitment in allergic asthma, we demonstrated that γ-T is an agonist and α-T is an antagonist of protein
kinase C (PKC). Moreover in our studies with adult humans, a 5-fold higher plasma α-T level associates
with better spirometry and a 5-fold increase in γ-T associates with lower spirometry (10 to 17% decrease in
FEV1); this occurred by age 21, suggesting that early in life, tocopherol isoforms may regulate development
and lung responses to environmental exposures. We propose a novel concept that early in life, α-T and γ-T
regulate the development of dendritic cells (DCs) and allergic disease. Consistent with our novel concept, we
demonstrated that supplementation of allergic pregnant mice with γ-T increased and α-T decreased pup
allergic responses and subsets of lung CD11b+CD11c+ subsets of DCs that are critical to initiation of allergic
inflammation. In addition, the inhibitory effect of α-T early in life was sustained in the pups. In vitro, γ-T
increased and α-T decreased numbers of bone-marrow-derived DCs, suggesting at least a regulatory function
of tocopherols on differentiation of DCs. Mechanisms for α-T and γ-T regulation of the development of DCs
and allergic responses are not known. Our long term goal is to identify mechanisms for α-T and γ-T regulation
of the development of DCs and allergic responses. As a step towards our long-term goal, our central
HYPOTHESIS is that early in life, α-T reduces and γ-T elevates mediators that regulate 1) allergic responses
and 2) CD11b+CD11c+ DC development and function during the initiation of allergic lung responses. We will
test our central hypothesis with the following aims: Aim 1. Test the hypothesis that maternal α-T reduces and
γ-T elevates offspring cytokines and growth factors that regulate development of DC and T cell responses to
allergen early in life. Aim 2. Test the hypothesis that α-T inhibits and γ-T elevates DC PKC activity during
CD11b+CD11c+ DC differentiation and activation and T cell PKC activity during DC activation of T cells.
Successful completion of these studies will have a significant impact on 1) our understanding of mechanisms
of α-T and γ-T regulation of DCs during development of allergies and 2) the design of clinical studies with α-T
and γ-T. Furthermore, these studies will provide a basis for design of interventions that significantly impac...

## Key facts

- **NIH application ID:** 10231818
- **Project number:** 3R01AI127695-05S1
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** JOAN M COOK-MILLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $437,672
- **Award type:** 3
- **Project period:** 2017-06-23 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10231818

## Citation

> US National Institutes of Health, RePORTER application 10231818, Tocopherol regulation of the development of responsiveness to allergen early in life (3R01AI127695-05S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10231818. Licensed CC0.

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