Food allergy is a growing public health concern. Regulatory T (Treg) cells play a pivotal role in tolerance to food allergens, however, the effects of maternal immune responses on the induction of Treg cell-mediated tolerance in offspring are poorly understood. We have recently found that maternal sensitization with allergen (ovalbumin; OVA or peanut) prevented food allergic responses in murine offspring, as indicated by a decrease in levels of food anaphylaxis, allergen-specific immunoglobulin (Ig) E, serum mouse mast cell proteinase 1, and intestinal mast cell expansion in response to epicutaneous sensitization and oral challenge with the same allergen. This protection was associated with an increase in levels of IgG and food allergen immune complexes (IgG-IC) and transforming growth factor (TGF) ? in breast milk. Neonatal Fc receptor (FcRn)-dependent transfer of maternal IgG-IC via breast milk and IgG-IC presentation by neonatal CD11c+ dendritic cells (DCs) promoted the differentiation of allergen-specific Treg cells in offspring. Breastfeeding by OVA-sensitized mothers or maternal supplementation with IgG-IC induced neonatal tolerance. Consistently, human breast milk collected from non-atopic mothers contained IgG-IC and induced tolerance in humanized FcRn mice. These results suggest that maternal IgG-IC in breast milk and offspring CD11c+ DCs are critical for the induction of Treg cell responses and control food-specific tolerance in neonates and that TGF? may facilitate this effect. Q576R mice, a genetic murine model of atopy, carry the naturally-occurring interleukin (IL)-4 receptor (IL-4R) ? chain Q576R polymorphism associated with asthma and atopic dermatitis in humans. Offspring of OVA-sensitized Q576R mothers showed a decrease in the frequencies of allergen-specific Treg cells and suboptimal levels of tolerance against food allergy as compared to wild-type controls. This partial protection was associated with lower levels of TGF? in breast milk and dysregulation of intestinal CD11c+ DCs in offspring. These results suggest that genetic predisposition of mothers and offspring to atopy may hinder optimal induction of neonatal tolerance via modulation of maternal TGF? and offspring DCs. The goals of this proposal are to decipher the time frame and the mechanistic interactions of maternal factors and offspring immune responses critical to establish effective food-specific tolerance in neonates, and how they are modulated by genetic susceptibilities to atopy. We hypothesize that exposure of neonatal DCs to sufficient levels of TGF? in breast milk during a specific time window in the perinatal period is critical to generate functional Treg cells specific to maternally transferred allergen IgG-IC in breast milk. We also hypothesize that excessive IL-4R signaling, a key signaling in the pro-allergic Th2 responses, modifies maternal TGF? levels and offspring DC phenotype, and induces the reprograming of Treg cells in offspring that hampers optimal induction of neonatal tolerance. These studies have the potential to identify interventional strategies to induce tolerance in early life to prevent food allergy in children.

Public Health Relevance

We recently found using a mouse model that mothers who mounted immune responses to food transfer antibodies to their babies in breast milk and induce regulatory T immune cells that mediate tolerance and protect children from food allergy, a major health problem that affects 8% of children and 5% of adults in the U.S. In this proposal, we aim to find how and when maternal factors in breast milk and immune cells in offspring interact to induce tolerance to food in children, and how they are modulated by genetic mutation linked to atopy. Our studies will support potential beneficial effects of maternal allergen exposure during breastfeeding on protecting babies from food allergy and will define how genetic factors affect tolerance induction in neonates, paving the way towards the design of therapies for prevention and treatment of food allergy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Davidson, Wendy F
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Boston Children's Hospital
United States
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