Induction of food allergen-specific neonatal tolerance through breast milk

项目摘要 食物过敏是一个日益严重的公共卫生问题。调节性T(Treg)细胞在耐受中发挥关键作用 食物过敏原，然而，母体免疫反应对Treg细胞介导的诱导的影响 人们对后代的耐受性知之甚少。我们最近发现，母亲对过敏原的致敏作用 (卵清蛋白；卵清蛋白或花生)预防小鼠后代的食物过敏反应，如减少所示 在食物过敏反应、变应原特异性免疫球蛋白(Ig)E、血清肥大细胞蛋白酶1、 和肠道肥大细胞对皮肤表面致敏和口服致敏的反应 过敏原。这种保护与免疫球蛋白和食物过敏原免疫复合体水平的增加有关。 母乳中的免疫球蛋白IC和转化生长因子β。新生儿Fc受体(FcRN)依赖 母血免疫球蛋白IC经母乳转移及新生儿CD11c+树突状细胞(DC)提呈免疫球蛋白IC 促进子代变应原特异性Treg细胞的分化。卵清蛋白致敏的母乳喂养 母亲或母亲补充免疫球蛋白IC可诱导新生儿耐受。一如既往地，人类母乳 在人源化FcRN小鼠中采集的非特应性母亲的血清中含有Ig G-IC并诱导免疫耐受。这些 结果提示，母血和子代CD11c+树突状细胞中的免疫球蛋白-IC在诱导母体免疫缺陷的发生中起关键作用 TREG细胞反应和控制新生儿的食物特异性耐受性，转化生长因子β可能促进这一作用。 Q576R小鼠是一种遗传性特应性小鼠模型，携带自然产生的白细胞介素4受体 (IL-4R)α链Q576R基因多态性与人类哮喘和特应性皮炎的关系的后代 卵子致敏的Q576R母亲表现出过敏原特异性Treg细胞和 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 与母乳中转化生长因子β水平降低和肠道CD11c+DC调节失调有关 后代。这些结果表明，母亲和子女对特应症的遗传易感性可能会阻碍 通过调节母体转化生长因子β和子代DC最佳诱导新生儿耐受。 这项提议的目标是破译时间框架和 母体因素和子代免疫反应对建立有效的食物特异性耐受性至关重要 以及他们是如何受到特应性遗传易感性的影响的。我们假设 新生儿DC在特定时间窗口内母乳中足够水平的转化生长因子β暴露 围产期是产生母体转移变应原特异性Treg细胞的关键 母乳。我们还假设，过度的IL-4R信号是促过敏Th2中的一个关键信号 反应，改变母体转化生长因子β水平和子代DC表型，并诱导Treg的重新编程 影响新生儿耐受性最佳诱导的子代细胞。这些研究有可能 确定在早期生活中诱导耐受性的干预策略，以预防儿童的食物过敏。

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.