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