Investigating the early development of the immune system and islet autoimmunity later in life

研究生命后期免疫系统的早期发育和胰岛自身免疫

• 批准号: 10186469
• 负责人: Li Wen
• 金额: $ 41.84万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-20 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10186469
• 关键词: Address; Affect; Antibiotics; Asthma; Autoantigens; Autoimmunity; Bacteria; Bacterial DNA; Birth; Childhood; DNA sequencing; Data; Developed Countries; Development; Diabetes Mellitus; Disease; Environment; Exposure to; Fetal Development; Fetus; Germ-Free; Goals; Health; Hypersensitivity; Immune; Immune Tolerance; Immune response; Immune system; Inbred NOD Mice; Incidence; Insulin-Dependent Diabetes Mellitus; Knowledge; Life; Methodology; Mus; Play; Pregnancy; Role; Shapes; Sterility; Systems Development; Testing; Uterus; commensal bacteria; fetal; gut bacteria; gut microbiota; intrauterine environment; islet; islet autoimmunity; maternal microbiota; neonate; offspring; oral commensal; peptidomimetics; pregnant; prenatal exposure; response

Abstract This resubmission is in response to PAR-18-333 “Understanding the Early Development of the Immune System”. Increasing evidence suggests that commensal bacteria play an important role in health and disease, including in pregnancy. Using advanced methodology, recent studies have indicated that the fetus may not live in a sterile environment. Our preliminary data using antibiotics suggest that commensal bacteria play an important role, during pregnancy, in shaping the early development of fetal immune tolerance to islet autoimmunity that may manifest later in life of the offspring. This has led us to hypothesize that removing the low number of commensal bacteria in the uterus may regulate the early development of fetal immune system and fetal immune programming to be tolerant or not, to islet autoimmunity. The overall goal of our proposal is to address an important gap in our knowledge and understanding of the role of maternal microbiota in influencing fetal immune system development and immune tolerance. We propose three specific aims to test our different but inter-connected hypotheses: Aim 1: To test the hypothesis that the mode of birth delivery contributes to the development/programming of the immune system of the neonates, which later affects development of immune tolerance later in life in non obese diabetic (NOD) mice; Aim 2: To test the hypothesis that fetal immune system development is associated with the presence of maternal commensal bacteria, using germ free (GF) NOD mice; Aim 3: To determine whether an oral commensal, which expresses an islet autoantigen mimic peptide, will influence immune tolerance to self antigen and autoimmunity, by maternal-fetal transfer and subsequent fetal immune system development in GF mice.

摘要 此次重新提交是对PAR-18-333“了解免疫的早期发展”的回应。 系统”。越来越多的证据表明，肠道细菌在健康和 疾病，包括怀孕。使用先进的方法，最近的研究表明， 胎儿不能生活在无菌环境中。我们使用抗生素的初步数据表明， 在怀孕期间，细菌在塑造胎儿免疫的早期发育方面发挥着重要作用。 对胰岛自身免疫的耐受性可能在后代的生命后期表现出来。这使我们 假设去除子宫内少量的细菌可以调节早期的 胎儿免疫系统的发育和胎儿免疫编程是否耐受， 自身免疫我们的提案的总体目标是填补我们知识上的一个重要空白， 了解母体微生物群在影响胎儿免疫系统发育中的作用， 免疫耐受我们提出了三个具体目标来测试我们不同但相互关联的假设： 目标1：检验分娩方式有助于发展/方案拟订的假设 新生儿的免疫系统，后来影响免疫耐受的发展，在以后的生活中， 目的2：检验胎儿免疫系统发育与非肥胖型糖尿病（NOD）小鼠的免疫功能相关的假说。 与母体肠道细菌的存在相关，使用无菌（GF）NOD小鼠;目的3： 确定表达胰岛自身抗原模拟肽的口服疫苗是否会影响 通过母-胎转移和随后的胎儿对自身抗原和自身免疫的免疫耐受 GF小鼠的免疫系统发育。