Breastmilk antibodies regulate neonatal immunity to the microbiota

母乳抗体调节新生儿对微生物群的免疫力

基本信息

批准号：
10568623
负责人：
Meghan Anne Koch
金额：
$ 64.34万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10568623
关键词：
Adult Animals Antibodies Antigen-Antibody Complex Antigens Area B-Lymphocytes Bacteria Benign Binding Breast Feeding CD4 Positive T Lymphocytes Cells Chemicals Colitis Complement Activation Complement Receptor Data Dendritic Cells Development Disease Education Equilibrium Fc Receptor Fc domain Flow Cytometry Food Fostering Goals Health Health Promotion Helper-Inducer T-Lymphocyte Homeostasis Human Human Milk Hypersensitivity IgG1 IgG3 Immune Immune System Diseases Immune response Immunity Immunoglobulin A Immunoglobulin G Immunologics Infant Inflammation Inflammatory Bowel Diseases Inflammatory Response Ingestion Intestines Knowledge Lactobacillus Lead Life Ligation Link Maternal antibody Mediating Metabolic dysfunction Milk Molecular Morbidity - disease rate Mothers Mucosal Immune Responses Mucosal Immune System Mucosal Immunity Mucous Membrane Mucous body substance Neonatal Oral Administration Ovalbumin Play Predisposition Process Production RANTES Research Role Severity of illness Shapes Signal Pathway Signal Transduction Site Solid Specificity Structure of germinal center of lymph node T cell response Testing Transgenic Mice Weaning Work XCR1 gene adaptive immune response antigen binding antimicrobial peptide cell type chemokine commensal bacteria commensal microbes dietary draining lymph node feeding gastrointestinal epithelium gut bacteria gut inflammation gut microbes host microbiota host-microbe interactions immune health innovation insight intestinal homeostasis mesenteric lymph node microbiota microorganism antigen mouse model mutualism neonatal immune system neonatal immunity neonate neutralizing antibody nutrition offspring pathogen prevent receptor function recruit resident commensals response restraint suckling transmission process wound

项目摘要

PROJECT SUMMARY To maintain health, the host must avoid generating inflammatory responses to beneficial gut bacteria, while retaining the ability to respond to pathogens. Maintaining this balance is particularly complicated in early life as many of the mechanisms that serve to promote tolerance to resident commensal microbes in adults are either absent or not yet established during this period. We recently identified maternal antibodies as key regulators of host-microbiota mutualism in neonates. Specifically, we found that in addition to IgA, healthy mothers generate microbiota-reactive IgG antibodies, which are transmitted via breastmilk and coat bacteria in the neonatal gut. In comparison with control offspring, neonates that do not receive these maternal isotypes harbor increased numbers of commensal bacteria in gut draining lymph nodes, mount inappropriate, microbiota-driven CD4 T- dependent immune responses, and suffer increased morbidity when subjected to a chemical form of colitis. Building from these exciting findings, this proposal seeks to understand the mechanisms by which maternal antibodies regulate nascent host-microbiota interactions in neonates. Specifically, we will determine the antigen specificities and the effector mechanisms (e.g., complement activation or Fc receptor ligation) required for distinct maternal IgG isotypes to restrain neonatal adaptive immune responses to beneficial gut bacteria. Additionally, we will define the signaling pathways and cell types required to trigger dysregulated adaptive immune responses in offspring that do not receive breastmilk antibodies. We will employ innovative approaches to achieve these goals by leveraging fostering and optimized infant feeding approaches with transgenic mouse models and multi-parameter flow cytometry. These studies are significant because they address key gaps in our knowledge regarding how favorable relationships between the host and resident microbiota are established in early life. Additionally, our work will also advance our understanding of the mechanisms by which breastfeeding promotes health. We expect that the insight gained from this research will significantly aid in our ability to manipulate host-microbiota interactions and mucosal immunity during early life, regardless of mode of nutrition.

项目概要为了保持健康，宿主必须避免对有益肠道细菌产生炎症反应，同时保留对病原体的反应能力。维持这种平衡在生命早期尤其复杂，因为许多有助于促进成人对常驻共生微生物的耐受性的机制是在此期间不存在或尚未建立。我们最近发现母体抗体是关键调节因子新生儿宿主-微生物群的互利共生。具体来说，我们发现除了 IgA 之外，健康的母亲还会产生微生物群反应性 IgG 抗体，通过母乳和新生儿肠道中的包被细菌传播。在与对照后代相比，未接受这些母体同种型的新生儿携带的基因增加肠道引流淋巴结中的共生细菌数量，安装不适当的、微生物群驱动的 CD4 T- 依赖的免疫反应，并且当遭受化学形式的结肠炎时发病率增加。基于这些令人兴奋的发现，该提案旨在了解母亲的机制抗体调节新生儿中新生宿主-微生物群的相互作用。具体来说，我们将确定抗原所需的特异性和效应机制（例如补体激活或 Fc 受体连接）不同的母体 IgG 同种型可抑制新生儿对有益肠道细菌的适应性免疫反应。此外，我们将定义触发适应性失调所需的信号传导途径和细胞类型未接受母乳抗体的后代的免疫反应。我们将采用创新方法通过利用转基因小鼠的培育和优化婴儿喂养方法来实现这些目标模型和多参数流式细胞术。这些研究意义重大，因为它们解决了我们在关于宿主和常驻微生物群之间如何建立良好关系的知识早期生活。此外，我们的工作还将增进我们对母乳喂养机制的理解促进健康。我们期望从这项研究中获得的见解将极大地帮助我们的能力无论营养模式如何，在生命早期控制宿主与微生物群的相互作用和粘膜免疫。