Maternal influence on offspring food allergy

母亲对后代食物过敏的影响

• 批准号: 10708905
• 负责人: Michiko Oyoshi
• 金额: $ 54.67万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708905
• 关键词: Adult; Affect; Alleles; Allergens; Allergic; Anaphylaxis; Animal Model; Antibiotics; Antibodies; Antigen-Antibody Complex; Bacteria; Basophils; Breast Feeding; CD4 Positive T Lymphocytes; Cell Differentiation process; Cells; Child; Chymase; DNA Sequence Alteration; Data; Failure; Fc Receptor; Food; Food Hypersensitivity; Fostering; Frequencies; Genes; Genetic; Genotype; Germ-Free; Goals; Human; Human Milk; ITGAX gene; IgE; Immune; Immune response; Immunoglobulin G; Impairment; Infant Food; Interleukin 4 Receptor; Intestines; Investigation; Lactation; Life; Link; Mediating; Mediator; Milk; Mothers; Mus; Neonatal; Oligosaccharides; Oral; Orphan; Ovalbumin; Pathway interactions; Pilot Projects; Population; Predisposition; Prevention strategy; Preventive; Process; Proteins; Public Health; Regulatory T-Lymphocyte; Retinoic Acid Receptor; Role; Serum; Shapes; Signal Transduction; Skin; Supplementation; Weaning; Wild Type Mouse; Work; allergic response; atopy; bacterial community; comparison control; design; effective therapy; experimental study; food allergen; gain of function mutation; global health; gut microbiota; in vivo; innovation; lactation period; mast cell; maternal microbiota; microbiota; mouse model; neonatal Fc receptor; neonate; offspring; prevent; receptor; response; tool

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 developed allergen-specific Rorγt+ Treg cells in the neonatal gut suppress Th2 responses to food allergen, and that this process is compromised by high Th2 signaling. We also hypothesize that the maternal microbiota during the lactation period shape the neonatal gut microbiota that induce the Treg cell-mediated neonatal food tolerance.

项目摘要 食物过敏（FA）是一个日益增长的公共卫生问题。母体免疫应答对诱导的影响 调节性T（Treg）细胞介导的后代食物耐受性的机制知之甚少。我们发现母亲 过敏原[卵清蛋白（OVA）或花生]的“保护性”致敏可预防小鼠后代的FA反应 对相同变应原的表皮致敏和口服激发的反应，如降低所示。 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 和肠肥大细胞的扩张。母体IgG和过敏原的新生儿Fc受体（FcRn）依赖性转移 通过乳汁的免疫复合物（IgG-IC）和新生儿CD 11 c+细胞诱导的过敏原特异性IgG-IC呈递 后代中的Treg细胞。未致敏母亲的后代由OVA致敏母亲或母亲IgG- IC补充诱导新生儿耐受。一致地，来自非特应性母亲的人乳含有 在人源化FcRn小鼠中IgG-IC和诱导的耐受性。这些结果表明，母乳IgG-IC-FcRn 轴建立了Treg细胞介导的新生儿食物耐受性，这可能延伸到人类。的延伸 我们以前的研究，这项建议的目标是以前调查不足的机制，额外的 乳因子（微生物群）除了IgG-IC在特定的断奶前间隔在哺乳期关键调节 维甲酸受体相关孤儿受体γt + Treg细胞介导新生儿免疫耐受的诱导 对抗FA。选择性删除 Rorγt的编码基因Rorc， 叉头盒蛋白3（Foxp 3）+ Treg细胞 在野生型（WT）小鼠中容易产生FA。 OVA致敏的WT母亲的后代显示出更高的 与对照相比，OVA特异性Rorγt+ Treg细胞。Il 4 raF 709小鼠是FA的鼠模型，携带获得性- 白细胞介素（IL）-4受体（IL-4 R）α链等位基因功能突变。Il 4 raF 709卵清蛋白致敏的子代 在IgG-IC存在下，与对照相比，Il 4 raF 709母亲显示对FA的耐受失败， 与Rorγt+ Treg细胞频率降低相关。用梭菌目或类杆菌目进行细菌治疗 种诱导Rorγt+ Treg细胞抑制IL 4 raF 709小鼠中的FA，表明Rorγt+ Treg细胞介导 对FA的保护和亲特应性基因型可能阻碍新生儿耐受的最佳诱导 通过Rorγt+ Treg细胞的重编程 . OVA致敏的无菌母体的后代和 在哺乳期接受抗生素治疗的OVA母亲未能显示出对FA的保护，即使在哺乳期， IgG-IC的存在。我们的初步研究确定了牛奶细菌类群和人乳的差异 非特应性和FA组之间的低聚糖。这些结果意味着， 哺乳期是成功诱导新生儿食物耐受所必需的。我们假设， 新生儿肠道中产生的过敏原特异性Rorγt+ Treg细胞抑制对食物过敏原的Th 2应答， 这一过程受到Th 2信号的影响。我们还假设，母亲的微生物群在 哺乳期形成新生儿肠道微生物群，诱导Treg细胞介导的新生儿食物耐受。