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 肠腔含有大量来自饮食和微生物群的蛋白质，需要耐受性 回应。如果没有正确地对这些无害蛋白质产生耐受性，粘膜免疫系统就会 不断遇到的情况下，人们逐渐面临包括食物在内的炎症性疾病的风险 过敏或炎症性肠病。随着这些疾病发病率的增加，特别是在 对于儿科人群，了解免疫系统在生命早期如何遇到管腔抗原必须 深入探索这些疾病的预防和治疗。目前，纯母乳喂养 是婴儿前三个月的推荐饮食习惯，然后补充辅食 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 全球范围内的婴儿在出生后的前三个月都是纯母乳喂养，并且替代性饮食包括婴儿配方奶粉和 使用羊奶的原因有多种。母乳喂养与食物风险降低显着相关 过敏和炎症性肠病以及母乳中的许多有益成分已被确定。我们之前有过 研究表明，表皮生长因子 (EGF) 在母乳中高度集中，尤其是在哺乳早期。 分娩后，EGF 会立即抑制新生儿肠道内的抗原传递，并且缺乏饮食 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 允许发生抗原递送，并且 FoxP3+ 调节性 T 细胞响应口服抗原而发育 这段时间。因此，母体 EGF 调节抗原传递，直到婴儿准备好 对遇到的抗原产生耐受性反应。我们的初步数据显示膳食 EGF 下降或 破坏新生儿肠细胞内的表皮生长因子受体会导致早期抗原的产生 分娩时，断奶时 FoxP3+ 调节性 T 细胞减少，并且易感性增加 结肠炎模型中的肠道炎症。有趣的是，虽然 FoxP3+ 调节性 T 细胞分化 这些细胞响应早期抗原递送而启动，最终失去了 FoxP3 表达，但仍保留在 肠，成为效应细胞。抗原递送也与 CX3CR1+ F4/80+ 的增加相关 抗原呈递细胞，然而新生儿抗原呈递细胞在抗原递送下游的作用 仍然未知。这些数据表明，在母体 EGF 调节不存在的情况下，早期抗原递送会受到干扰 生命早期的口服耐受性。这里我们将1)确定新生儿抗原递送对抗原的影响 结肠中的呈递细胞，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生命早期的抗原传递受到以下因素的调节具有重要意义： 母乳，以及在缺乏母亲调节的情况下早期抗原输送的后果。