Immune Outcomes to Neonatal Antigen Delivery in the Intestine

新生儿肠道抗原传递的免疫结果

• 批准号: 10731505
• 负责人: Kathryn A Knoop
• 金额: $ 38.85万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10731505
• 关键词: Adolescent; Age; Allergic; Antigen-Presenting Cells; Antigens; Biological Assay; Breast Feeding; Cells; Childhood; Coculture Techniques; Colitis; Colon; Crohn' s disease; Curiosities; Data; Dendrites; Diet; Dietary Practices; Disease; Effector Cell; Environment; Epidermal Growth Factor; Epidermal Growth Factor Receptor; Epigenetic Process; Epithelium; Exclusive Breastfeeding; FOXP3 gene; Food; Food Hypersensitivity; Gastrointestinal tract structure; Goat; Goblet Cells; Grant; Growth Factor Inhibition; Health; Human; Human Milk; Immune; Immune response; Immune system; In Vitro; Incidence; Individual; Infant; Infant formula; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Interleukin-10; Intestinal permeability; Intestines; Kinetics; Lactation; Life; M cell; Macrophage; Maps; Mediating; Milk; Modeling; Mothers; Mucosal Immune System; Mucositis; Mus; Neonatal; Oral; Outcome; Peripheral; Phase; Phenotype; Population; Predisposition; Prevention; Process; Production; Proteins; Publishing; Recommendation; Regulation; Regulatory T-Lymphocyte; Risk; Role; Small Intestines; Solid; System; T cell differentiation; T-Lymphocyte; Testing; Time; Ulcerative Colitis; Weaning; Work; World Health Organization; conditional knockout; dietary; gut inflammation; in vivo; microbiota; neonate; oral tolerance; response; transcriptome sequencing

PROJECT ABSTRACT The intestinal lumen contains a plethora of proteins from the diet and microbiota that require tolerogenic responses. If tolerance is not properly mounted against these innocuous proteins the mucosal immune system constantly encounters, individuals become progressively at-risk for inflammatory disorders including food allergies or inflammatory bowel diseases. As these disorders increase in incidence, particularly within the pediatric population, understanding how the immune system encounters luminal antigens during early life must be thoroughly explored for the prevention and treatment of these disorders. Currently, exclusive breastfeeding is the recommended dietary practice for infants through the first three months, followed by complementary breastfeeding with introduction of solid foods. Yet the world health organization estimates only 30% of infants globally are exclusively breastfed in the first three months, and alternative diets ranging from infant formula to goat’s milk are used for a variety of reasons. Breastfeeding is significantly associated with decreased risk of food allergy and IBD, and a number of beneficial components of breast milk have been identified. We have previously shown epidermal growth factor (EGF) is highly concentrated in breastmilk, particularly early in lactation. Immediately following delivery, EGF inhibits antigen delivery within the neonates intestine, and a lack of dietary EGF is associated with increased intestinal permeability. As the infant ages, EGF in breastmilk decreases allowing antigen delivery to occur and FoxP3+ regulatory T cells develop in response to orally derived antigens during this time. Thus, maternal EGF regulates antigen delivery until a time when the infant is prepared to develop tolerogenic responses to encountered antigen. Our preliminary data shows decreased dietary EGF or disrupting the Epidermal Growth Factor Receptor within intestinal cells of the neonate resulted in early antigen delivery, decreased FoxP3+ regulatory T cells at the time of weaning, and an increased predisposition to intestinal inflammation in a model of colitis. Interestingly, while FoxP3+ regulatory T cell differentiation was initiated in response to early antigen delivery, these cells eventually lost FoxP3 expression but remained in the intestine, becoming effector cells. Antigen delivery was also associated with an increase in CX3CR1+ F4/80+ antigen presenting cells, however the role neonatal antigen presenting cells downstream of antigen delivery remains unknown. These data suggest early antigen delivery in the absence of maternal EGF regulation disrupts oral tolerance during early life. Here we will 1) determine the effect of neonatal antigen delivery on antigen presenting cells in the colon and 2) determine the mechanism through which neonatal antigen delivery abrogates regulatory T cells. This work has important implication in why antigen delivery during early life is regulated by breast milk, and the consequences of early antigen delivery in the absence of maternal regulation.

项目摘要 肠腔含有来自饮食和微生物群的过多蛋白质，需要耐受性 应答如果对这些无害的蛋白质的耐受性没有适当地建立， 不断接触，个人变得越来越有风险的炎症性疾病，包括食物 过敏或炎症性肠病。由于这些疾病的发病率增加，特别是在 儿童群体，了解免疫系统如何遇到管腔抗原在生命早期必须 对这些疾病的预防和治疗进行彻底的探索。目前，纯母乳喂养 是婴儿前三个月的推荐饮食习惯，其次是补充 母乳喂养并引入固体食物。然而世界卫生组织估计只有30%的婴儿 在全球范围内，婴儿在头三个月内完全接受母乳喂养， 山羊奶的使用有很多原因。母乳喂养与食物风险降低显著相关 过敏和IBD，以及母乳中的一些有益成分已经被确定。我们先前已经 表皮生长因子（EGF）在母乳中高度集中，特别是在哺乳早期。 在分娩后，EGF抑制了新生儿肠道内的抗原递送，并且缺乏饮食刺激。 EGF与肠道通透性增加有关。随着婴儿年龄的增长，母乳中的EGF会减少。 允许抗原递送发生并响应口服衍生抗原而发育FoxP 3+调节性T细胞 这段时间因此，母体EGF调节抗原递送，直到婴儿准备好 对遇到的抗原产生耐受性应答。我们的初步数据显示，减少饮食EGF或 破坏新生儿肠细胞内的表皮生长因子受体， 分娩时，断奶时FoxP 3+调节性T细胞减少， 结肠炎模型中的肠道炎症。有趣的是，虽然FoxP 3+调节性T细胞分化是一种免疫调节。 这些细胞在早期抗原递送的应答中启动，最终失去FoxP 3表达，但仍保持在 肠，成为效应细胞。抗原递送也与CX 3CR 1 + F4/80+的增加相关。 然而，抗原呈递细胞在抗原递送下游的新生儿抗原呈递细胞的作用 仍然未知。这些数据表明，在缺乏母体EGF调节的情况下， 早期的口服耐受性。在这里，我们将1）确定新生儿抗原输送对抗原的影响 结肠中的呈递细胞和2）确定新生儿抗原递送废除的机制 调节性T细胞这项工作对于解释为什么早期生命中的抗原递送是由 母乳，以及在缺乏母体调节的情况下早期抗原递送的后果。