Induction of food allergen-specific neonatal tolerance through breast milk

通过母乳诱导新生儿对食物过敏原特异性耐受

• 批准号: 10059170
• 负责人: Michiko Oyoshi
• 金额: $ 50.61万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2021-03-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10059170
• 关键词: Adult; Affect; Allergens; Allergic; Anaphylaxis; Animals; Antibodies; Antigen-Antibody Complex; Antigens; Asthma; Atopic Dermatitis; Basophils; Breast Feeding; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Child; Chymase; Complement Factor B; DNA Sequence Alteration; Dendritic Cells; Disease; Fc Receptor; Food; Food Hypersensitivity; Frequencies; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Goals; Health; Human; Human Milk; ITGAX gene; IgE; Immune; Immune response; Immunoglobulin G; Impairment; Infant Food; Interleukin 4 Receptor; Interleukins; Intervention; Intestines; Investigation; Life; Link; Maintenance; Mediating; Mediator of activation protein; Milk; Mothers; Mus; Neonatal; Oral; Ovalbumin; Pathogenicity; Phenotype; Play; Population; Prevention therapy; Process; Production; Public Health; Regulatory T-Lymphocyte; Role; Sampling; Serum; Signal Transduction; Supplementation; Time; Transforming Growth Factor beta; Transforming Growth Factors; Weaning; Work; allergic response; antibody transfer; atopy; cytokine; experimental study; food allergen; in vivo; mast cell; mouse model; neonatal Fc receptor; neonatal exposure; neonatal immune system; neonatal period; neonate; offspring; perinatal period; prevent; programs; response; therapy design; tool

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.

项目摘要 食物过敏是日益增长的公共卫生问题。调节t（Treg）细胞在耐受性中起关键作用 然而，食品过敏原对孕产妇免疫反应对Treg细胞介导的诱导的影响 后代的宽容知之甚少。我们最近发现对过敏原的材料敏感性 （椭圆蛋白；卵子或花生）防止食物后代的食物过敏反应，如减少所示 在食物过敏反应的水平中，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， 以及对表皮敏感性和口服挑战的肠道肥大细胞的扩张 过敏原。这种保护与IgG和食物过敏原免疫复合物的水平增加有关 （IgG-IC）和母乳中转化生长因子（TGF）β。新生儿FC受体（FCRN）依赖性 新生儿CD11C+树突状细胞（DCS）通过母乳和IgG-IC表示母体IgG-IC的转移 促进了后代过敏原特异细胞的分化。 OVA敏感的母乳喂养 母亲或接受IgG-IC诱导的新生儿耐受性的母亲或母子补充。一贯，人类母乳 从非原子母亲收集的人源化FCRN小鼠中包含IgG-IC和诱导的耐受性。这些 结果表明，母乳和后代CD11C+ DC中的Mater IgG-IC对于诱导至关重要 TREG细胞反应和控制新生儿的食物特异性耐受性，TGFβ可能有助于这种影响。 Q576R小鼠是一种遗传鼠（一种遗传鼠），携带天然的白介素（IL）-4接收器 （IL-4R）α链Q576R多态性与人类哮喘和特应性皮炎有关。后代 OVA敏感的Q576R母亲显示出过敏原特异细胞和 与野生型对照相比，对食物过敏的耐受性次优水平。这种部分保护 与母乳中TGFβ水平较低有关，肠CD11C+ DC的失调 后代。这些结果表明，母亲和后代的遗传易感性可能会阻碍 通过调节母体TGFβ和后代DC的最佳诱导新生儿耐受性。 该提案的目标是破译时间范围和机械互动 产妇因素和后代免疫反应至关重要 在新生儿，以及如何通过遗传敏感性调节它们。我们假设这一点 在特定时间窗口中，新生儿DC暴露于母乳中足够水平的TGFβ水平 围产期对于产生特异性特异性的特异性Treg细胞至关重要。 母乳。我们还假设超级IL-4R信号传导，这是pro或过敏性TH2中的键信号传导 响应，修改MaterTGFβ水平和后代DC表型，并诱导Treg重新编程 后代的细胞会阻碍新生儿耐受性的最佳诱导。这些研究有可能 确定介入早期耐受性的介入策略，以防止儿童的食物过敏。