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.

母儿免疫应答的关系 胎儿免疫系统在妊娠第三周开始发育，并一直发展到出生。在此 同时，它受母亲事件的影响很大。接触艾滋病毒的未感染婴儿（HEU）提供了一个很好的 与未暴露于HIV的新生儿相比，出生时新生儿具有多种免疫学差异的示例 未感染的婴儿（HUU）持续数月至数年，尽管没有HIV感染，但仍会导致 严重感染、住院和死亡的风险增加。其他产妇的医疗条件也会影响 胎儿免疫系统，如慢性乙型肝炎B感染，1型糖尿病和肥胖症。机制 母体和胎儿免疫系统通过什么途径进行交流尚不清楚。我们假设胎儿 免疫系统通过小分子或纳米颗粒接收来自母亲的指令 导致母胎二联体之间常见的免疫学偏差。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）作为潜在的 母体和胎儿免疫系统之间相互作用的介质。为了验证这个假设，我们将 利用先前NIAID中收集的来自感染和未感染HIV的女性的配对CBMC和母体PBMC- 资助的研究。在目前的研究中，我们制定了以下具体目标： 目标1.为了确定有和没有免疫缺陷的母亲所共有的免疫学特征的广度， 艾滋病毒和胎儿。 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细胞和抗原呈递细胞的表观遗传谱， 由母体-胎儿二分体共享，对于HEU和HUU二分体而言是独特的和共同的。 目标二。鉴定代谢物、母体激素、细胞因子/趋化因子和/或EV， 区分高浓缩铀和高浓缩铀的母体-胎儿二分体。 我们将描述母体和胎儿的代谢组学、蛋白质组学、激素和EV血浆谱，以确定 母胎二分体共有的因素。然后，我们将确定那些专门针对高浓缩铀的措施， 与HUU dyads相比。 目标3.确定母体和胎儿免疫系统之间的通讯介质。 使用transwell系统模拟胎盘屏障，我们将检查功能和表型变化 在母体因素诱导的Treg CBMC中。 冲击我们将研究母胎信息传递程序的人类胎儿免疫系统。这 是设计干预措施以减轻胎儿免疫功能障碍的关键步骤。通过利用来自 在NIAID资助的研究之前，我们将能够使用多组学来最大限度地提高这些开创性研究的深度。