Maternal influence on offspring food allergy

母亲对后代食物过敏的影响

基本信息

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
项目类别：
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

项目摘要

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.

项目概要食物过敏 (FA) 是一个日益受到关注的公共卫生问题母体免疫反应对引产的影响。我们发现母体对调节性 T (Treg) 细胞介导的食物耐受性的影响知之甚少。过敏原 [卵清蛋白 (OVA) 或花生] 的“保护性”致敏可阻止小鼠后代的 FA 反应响应相同过敏原的表皮致敏和口腔挑战，如减少所示食物过敏反应、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 的水平，新生儿 Fc 受体 (FcRn) 依赖性母体 IgG 和过敏原的转移。免疫复合物 (IgG-IC) 通过乳汁和新生儿 CD11c+ 细胞诱导的过敏原特异性呈递 IgG-IC 由 OVA 致敏母亲或母体 IgG- 培养的未致敏母亲的后代中的 Treg 细胞。一致地，非特应性母亲的母乳中含有 IC 补充剂。 IgG-IC 和人源化 FcRn 小鼠中诱导的耐受性这些表明母乳 IgG-IC-FcRn 的结果。建立 Treg 细胞介导的新生儿食物耐受性轴，该轴可能延伸到人类。我们之前的研究表明，该提案的目标是以前未充分调查的机制，通过该机制可以增加额外的除了 IgG-IC 之外，在哺乳期间的特定断奶前间隔中，牛奶因子（微生物群）也能严格调节诱导视黄酸受体相关孤儿受体 γt (Rorγt)+ Treg 细胞介导的新生儿耐受反对FA.选择性删除 Rorc，编码 Rorγt 的基因，位于叉头盒蛋白 3 (Foxp3)+ Treg 细胞野生型 (WT) 小鼠易患 FA。 OVA 敏感的 WT 母亲的后代表现出更高的频率与对照小鼠相比，OVA 特异性 Rorγt+ Treg 细胞（FA 小鼠模型）具有增益。 OVA 致敏的白细胞介素 (IL)-4 受体 (IL-4R) α 链等位基因 Il4raF709 后代的功能突变。在 IgG-IC 存在的情况下，与对照相比，Il4raF709 母亲表现出对 FA 的耐受失败，与梭菌目或拟杆菌目细菌治疗中 Rorγt+ Treg 细胞频率降低有关。物种诱导的 Rorγt+ Treg 细胞抑制了 Il4raF709 小鼠中的 FA，表明 Rorγt+ Treg 细胞介导针对 FA 的保护作用以及促特应性基因型可能会阻碍新生儿耐受性的最佳诱导通过 Rorγt+ Treg 细胞的重编程 OVA 致敏的无菌母亲的后代和 . 在哺乳期接受抗生素治疗的 OVA 母亲未能表现出针对 FA 的保护作用，即使在哺乳期也是如此。我们的初步研究确定了牛奶细菌分类群和母乳中的差异。这些结果表明母体微生物群在非特应性组和 FA 组之间存在差异。哺乳期对于成功诱导新生儿食物耐受是必要的。在新生儿肠道中发育出过敏原特异性 Rorγt+ Treg 细胞，抑制 Th2 对食物过敏原的反应，并且我们还认为这一过程受到高 Th2 信号传导的影响。哺乳期塑造新生儿肠道微生物群，诱导 Treg 细胞介导的新生儿食物耐受性。