# Maternal influence on offspring food allergy

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $534,497

## Abstract

Project Summary
Food allergy (FA) is a growing public health concern. The effects of maternal immune responses on the induction
of regulatory T (Treg) cell-mediated food tolerance in offspring are poorly understood. We found that maternal
“protective” sensitization with allergen [ovalbumin (OVA) or peanut] prevented FA responses in murine offspring
in response to epicutaneous sensitization and oral challenge with the same allergen, as indicated by a decrease
in the levels of food anaphylaxis, allergen-specific immunoglobulin (Ig) E, serum mouse mast cell proteinase 1,
and intestinal mast cell expansion. Neonatal Fc receptor (FcRn)-dependent transfer of maternal IgG and allergen
immune complexes (IgG-IC) via milk and IgG-IC presentation by neonatal CD11c+ cells induced allergen-specific
Treg cells in offspring. Offspring of unsensitized mothers fostered by OVA-sensitized mothers or maternal IgG-
IC supplementation induced neonatal tolerance. Consistently, human milk from non-atopic mothers contained
IgG-IC and induced tolerance in humanized FcRn mice. These results indicate that maternal milk IgG-IC-FcRn
axis establishes Treg cell-mediated neonatal food tolerance, which may extend to humans. As an extension of
our prior study, the goals of this proposal are the previously underinvestigated mechanisms by which additional
milk factor (microbiota) besides IgG-ICs in a specific preweaning interval during lactation critically regulate the
induction of retinoic acid receptor related orphan receptor γt (Rorγt)+ Treg cell-mediated neonatal tolerance
against FA. Selective deletion of
Rorc, the gene encoding Rorγt, in
Forkhead box protein 3 (Foxp3)+ Treg cells
predisposes to FA in wild-type (WT) mice.
Offspring of OVA-sensitized WT mothers show higher frequencies of
OVA-specific Rorγt+ Treg cells as compared to controls. Il4raF709 mice, a murine model of FA, carry a gain-of-
function mutation in the interleukin (IL)-4 receptor (IL-4R) α chain allele. Il4raF709 offspring of OVA-sensitized
Il4raF709 mothers showed failure of tolerance towards FA as compared to controls in the presence of IgG-IC,
associated with decreased frequencies of Rorγt+ Treg cells. Bacteriotherapy with Clostridiales or Bacteroidales
species induced Rorγt+ Treg cells that suppressed FA in Il4raF709 mice, suggesting that Rorγt+ Treg cells mediate
protection against FA and that pro-atopic genotype may hinder the optimal induction of neonatal tolerance
through the reprogramming of Rorγt+ Treg cells
. Offspring of OVA-sensitized germ-free mothers and offspring of
OVA-mothers treated with antibiotics during the lactation period failed to show protection against FA, even in the
presence of IgG-IC. Our pilot study identified the differences in milk bacterial taxa and human milk
oligosaccharides between non-atopic and FA groups. These results imply that the maternal microbiota during
the lactation period is necessary to successfully induce neonatal food tolerance. We hypothesize that newly
devel...

## Key facts

- **NIH application ID:** 10877152
- **Project number:** 5R01AI172938-03
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Michiko Oyoshi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $534,497
- **Award type:** 5
- **Project period:** 2022-09-21 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877152

## Citation

> US National Institutes of Health, RePORTER application 10877152, Maternal influence on offspring food allergy (5R01AI172938-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877152. Licensed CC0.

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