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

• 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
• 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

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.

项目摘要 为了保持健康，宿主必须避免对有益的肠道细菌产生炎症反应， 保持对病原体的反应能力。维持这种平衡在早期生活中特别复杂， 许多促进成人对体内常驻微生物耐受的机制是 在这段时间内没有或尚未建立。我们最近发现母体抗体是 新生儿中的宿主-微生物群共生。具体来说，我们发现，除了伊加，健康的母亲产生 微生物群反应性IgG抗体，通过母乳和新生儿肠道中的外套细菌传播。在 与对照后代相比，没有接受这些母体同种型的新生儿的发病率增加， 肠道引流淋巴结中的肠道细菌数量，安装不当，微生物群驱动的CD 4 T- 依赖性免疫应答，并且当经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，这项提案旨在了解孕产妇死亡的机制。 抗体调节新生儿中的新生宿主-微生物群相互作用。具体来说，我们将确定抗原 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，以抑制新生儿对有益肠道细菌的适应性免疫应答。 此外，我们将定义触发失调的适应性细胞所需的信号通路和细胞类型。 没有接受母乳抗体的后代的免疫反应。我们将采用创新的方法 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 关于宿主和居民微生物群之间如何建立有利关系的知识， 早年生活此外，我们的工作还将促进我们对母乳喂养机制的理解， 促进健康。我们希望从这项研究中获得的见解将大大有助于我们的能力， 在生命早期操纵宿主-微生物群相互作用和粘膜免疫，无论营养模式如何。