Induction of food allergen-specific neonatal tolerance through breast milk

项目摘要 食物过敏是一个日益增长的公共卫生问题。调节性T（Treg）细胞在免疫耐受性中起关键作用。 然而，食物过敏原，母体免疫应答对Treg细胞介导的诱导的影响， 对后代的耐受性知之甚少。我们最近发现母体过敏原 （卵清蛋白; OVA或花生）预防小鼠后代的食物过敏反应，如减少 在食物过敏反应、过敏原特异性免疫球蛋白（IG）E、血清小鼠肥大细胞蛋白酶1 以及肠肥大细胞对表皮致敏反应的扩增和用其进行的口服激发 过敏原这种保护与IgG和食物过敏原免疫复合物水平的增加有关 （IgG-IC）和转化生长因子（TGF）β。新生儿Fc受体（FcRn）依赖性 母亲IgG-IC通过母乳的转移和新生儿CD11c+树突状细胞（DCs）的IgG-IC呈递 促进后代中变应原特异性Treg细胞的分化。OVA致敏的母乳喂养 母亲或母体补充IgG-IC诱导新生儿耐受。一致性，人母乳 从非特应性母亲收集的含有IgG-IC的抗体在人源化FcRn小鼠中诱导耐受性。这些 结果表明，母乳中的母体IgG-IC和后代CD11c + DCs对诱导 Treg细胞反应和控制新生儿的食物特异性耐受，TGF β可能促进这种作用。 Q576R小鼠是遗传性特应性小鼠模型，携带天然存在的白细胞介素（IL）-4受体 （IL-4R）α链Q576R多态性与人类哮喘和特应性皮炎相关后代 OVA致敏的Q576R母亲表现出过敏原特异性Treg细胞的频率降低， 与野生型对照相比，对食物过敏的耐受性低于最佳水平。这种局部保护 与母乳中TGF β水平较低和肠道CD11c + DCs失调有关， 后代这些结果表明，遗传易感性的母亲和后代的特应性可能会阻碍 通过调节母体TGF β和后代DC最佳诱导新生儿耐受。 该提案的目标是破译的时间框架和机械的相互作用， 母体因素和后代免疫应答对建立有效的食物特异性耐受至关重要 在新生儿中，以及它们如何被遗传易感性调节为特应性。我们假设 在特定的时间窗内，新生儿DC暴露于母乳中足够水平的TGF β， 围产期对于产生对母体转移的过敏原IgG-IC具有特异性的功能性Treg细胞至关重要， 母乳。我们还假设过度的IL-4R信号传导，促过敏性Th2细胞中的关键信号传导， 反应，改变母体TGF β水平和后代DC表型，并诱导Treg重编程 这些细胞在后代中阻碍新生儿耐受性的最佳诱导。这些研究有可能 确定干预策略，在生命早期诱导耐受性，以预防儿童食物过敏。

Project Summary 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) β 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 TGFβ may facilitate this effect. Q576R mice, a genetic murine model of atopy, carry the naturally-occurring interleukin (IL)-4 receptor (IL-4R) α 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 TGFβ 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 TGFβ 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 TGFβ 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 TGFβ 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.