Relationship between maternal and fetal immune responses

母体和胎儿免疫反应之间的关系

• 批准号: 10706532
• 负责人: ADRIANA WEINBERG
• 金额: $ 48.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-19 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706532
• 关键词: ATAC-seq; Affect; Antigen-Presenting Cells; Bioinformatics; Biology; Birth; Blood; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Cessation of life; Characteristics; Chronic Hepatitis B; Communication; Diabetes Mellitus; Ensure; Epigenetic Process; Event; Exposure to; FOXP3 gene; Fetus; Flow Cytometry; Frequencies; Funding; Genetic Transcription; HIV; HIV Infections; HIV-exposed uninfected infant; Hepatitis B Infection; Hormonal; Hormones; Hospitalization; IL2RA gene; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Immunology; Infant; Infection; Instruction; Insulin-Dependent Diabetes Mellitus; Intervention; Mediator; Medical; Membrane; Mononuclear; Mothers; National Institute of Allergy and Infectious Disease; Obesity; Peripheral Blood Mononuclear Cell; Phenotype; Placenta; Placental Hormones; Plasma; Pregnancy; Proteomics; Regulatory T-Lymphocyte; Resources; Risk; Scientist; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Umbilical Cord Blood; Woman; chemokine; cytokine; extracellular vesicles; fetal; high dimensionality; metabolomics; monolayer; multiple omics; nanoparticle; neonate; programs; small molecule; success; transcriptomics

Relationship between maternal and fetal immune responses The fetal immune system starts to develop in the third week of gestation and progresses until birth. During this time, it is greatly influenced by maternal events. HIV-exposed uninfected infants (HEU) provide an excellent example in which neonates at birth have multiple immunologic differences compared with HIV-unexposed uninfected infants (HUU) that persist for months to years and, despite the absence of HIV infection, result in an increased risk of severe infection, hospitalization and death. Other maternal medical conditions can also affect the fetal immune system, such as chronic hepatitis B infection, type 1 diabetes and obesity. The mechanism whereby the maternal and fetal immune systems communicate is not known. We hypothesized that the fetal immune system receives instructions from the mother through small molecules or nanoparticles resulting in common immunologic biases between maternal-fetal dyads. In this study, we will investigate maternal metabolites, cytokines/chemokines, placental hormones and extracellular vesicles (EV) as potential mediators of the cross talk between maternal and fetal immune systems. To test this hypothesis, we will leverage paired CBMC and maternal PBMC from women with and without HIV collected in a previous NIAID- funded study. In the current study, we formulated the following Specific Aims: Aim 1. To determine the breadth of the immunologic characteristics shared by mothers with and without HIV and their fetuses. Using high-dimensional flow cytometry, Cite-seq and ATAC-seq we will determine the phenotypic, transcriptomic and epigenetic profiles of maternal and fetal T cells and antigen presenting cells and identify characteristics shared by mother-fetus dyads both unique and common to HEU and HUU dyads. Aim 2. To identify metabolites, maternal hormones, cytokines/chemokines and/or EV shared by maternal-fetal dyads that distinguish HEU from HUU dyads. We will characterize maternal and fetal metabolomic, proteomic, hormonal and EV plasma profiles to identify the factors that are shared between maternal-fetal dyads. We will then identify those that are specific to HEU compared with HUU dyads. Aim 3. To identify mediators of the communication between the maternal and fetal immune systems. Using a transwell system to simulate the placental barrier, we will examine functional and phenotypic changes in the Treg CBMC induced by maternal factors. Impact. We will study maternal-fetal information transfer that programs the HUMAN fetal immune system. This is a critical step in devising interventions to mitigate fetal immune dysfunctions. By leveraging resources from a prior NIAID-funded study, we will be able to use multi-omics to maximize the depth of these pioneering studies.

产妇免疫反应之间的关系 胎儿免疫系统在妊娠的第三周开始发展，并一直延续到出生。在此期间 时间，它受到母性事件的极大影响。艾滋病毒暴露的未感染婴儿（HEU）提供了极好的 与HIV无暴露 持续数月至数年的未感染婴儿（HUU），尽管没有HIV感染，但 严重感染，住院和死亡的风险增加。其他母亲的医疗状况也会影响 胎儿免疫系统，例如慢性丙型肝炎感染，1型糖尿病和肥胖症。机制 尚不清楚母体和胎儿免疫系统传达。我们假设胎儿 免疫系统通过小分子或纳米颗粒从母亲那里收到指示 导致母亲二元组之间存在常见的免疫偏见。在这项研究中，我们将调查 母体代谢物，细胞因子/趋化因子，胎盘激素和细胞外囊泡（EV）作为潜力 孕产妇和胎儿免疫系统之间的串扰介体。为了检验这一假设，我们将 在先前的NIAID中收集和没有HIV的女性，利用有或没有HIV的妇女配对的CBMC和母体PBMC 资助研究。在当前的研究中，我们制定了以下特定目的： 目的1。确定母亲有和没有的母亲共享的免疫学特征的广度 艾滋病毒及其胎儿。 使用高维流式细胞术，Cite-Seq和ATAC-Seq，我们将确定表型，转录组学 以及母体和胎儿T细胞以及抗原呈现细胞的表观遗传学特征，并确定特征 由母亲和二元组的母亲和二元组共享。 目标2。鉴定代谢物，母体激素，细胞因子/趋化因子和/或EV共享 将Heu与Huu Dyads区分开的母亲二元组。 我们将表征孕妇和胎儿代谢组，蛋白质组学，激素和EV血浆曲线，以鉴定 产妇二元组之间共享的因素。然后，我们将确定那些特定于HEU的人 与Huu Dyads相比。 目的3。确定母体和胎儿免疫系统之间交流的介体。 使用Transwell系统模拟胎盘屏障，我们将检查功能和表型变化 在孕产妇因素引起的Treg CBMC中。 影响。我们将研究对人类胎儿免疫系统进行编程的母亲信息转移。这 是设计干预措施以减轻胎儿免疫功能障碍的关键步骤。通过利用资源 事先通过NIAID资助的研究，我们将能够使用多摩师来最大程度地提高这些开拓性研究的深度。