T cell activation and the breakdown of maternal-fetal tolerance in preterm labor

早产中 T 细胞激活和母胎耐受性崩溃

• 批准号: 9079351
• 负责人: Tippi Mackenzie
• 金额: $ 39.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-15 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9079351
• 关键词: 37 weeks gestation; Accounting; African American; Allogenic; Allograft Tolerance; Animal Model; Antigen Presentation; Antigens; Applications Grants; Biological Assay; Biology; Blood; Blood specimen; Cell Maturation; Cells; Clinical; Country; Decidua; Dendritic Cells; Development; Disease; Environment; Eragrostis; European; Failure; Fetus; Financial cost; Future; General Population; Goals; Health; Health Care Costs; Human; Immune response; Immune system; Immunologics; Incidence; Infant Mortality; Infection; Inflammation; Inflammatory; Institution; Intervention; Lead; Life; Listeria monocytogenes; Listeriosis; Lymphocyte; Maternal-Fetal Exchange; Measures; Mediating; Memory; Mixed Lymphocyte Culture Test; Modeling; Mothers; Mus; Neonatal; Neonatal Mortality; Operative Surgical Procedures; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Placenta; Population; Pregnancy; Pregnancy Complications; Premature Birth; Premature Infant; Premature Labor; Production; Public Health; Reading; Regulatory T-Lymphocyte; Reporter; Reporting; Research; Risk; Role; Sampling; Secondary to; Specificity; Sterility; T cell response; T-Cell Activation; T-Cell Development; T-Cell Proliferation; T-Cell Receptor; T-Lymphocyte; Testing; Time; Tissues; Umbilical Cord Blood; United States; Uterus; Woman; base; congenital anomaly; cytokine; effective therapy; embryo/fetus antigen; experience; fetal; fetal inflammatory response syndrome; fetus surgery; insight; mouse model; neonatal morbidity; novel; novel therapeutics; pregnant; prevent; research study; response; targeted treatment; therapeutic target; tool

 DESCRIPTION (provided by applicant): Preterm birth (defined as delivery before 37 weeks of gestation) is the most important cause of neonatal morbidity and mortality in the developed world and its incidence continues to rise. Current treatments have limited efficacy because the fundamental mechanisms leading to labor-whether term or preterm-are not known. Since successful pregnancy depends on multi-layered tolerance between the mother and the fetus, pregnancy complications may involve a breakdown in such mechanisms. We propose to examine the novel hypothesis that infection or inflammation during pregnancy results in the activation of maternal T cells specific for fetal or placental antigens, and of fetal T cells speciic for maternal antigens, ultimately resulting in rejection and preterm delivery. We will use mouse models and patient samples to test this hypothesis. In our mouse model, we have previously shown that fetal intervention (a model of sterile inflammation) activates maternal T cells that are specific for fetal antigens and that this activation can cause selective demise of allogeneic fetuses. This finding is consistent with other reports of T cell activation and fetal loss during Listeria infection in pregnant mice. We will now delineate the cellular mechanisms of these findings using a novel Nur77-Foxp3 double reporter mouse that tracks T cell receptor engagement in both effector and regulatory T cells. In our patient samples, we have developed robust assays to enumerate allospecific T cells to examine their possible contribution to clinical preterm labor (PTL). We made the surprising discovery that T cell proliferation in maternal blood is blunted during pregnancy but that fetal (cord blood) T cells are activated in patients with PTL secondary to infection. We propose to examine whether maternal T cells in the maternal tissue layer in contact with the placenta (the decidua) become activated during PTL, and the mechanisms leading to early activation of fetal T cells, in patients with PTL secondary to infection or fetal intervention. The latter is commonly performed at our institution to treat fetuss with congenital anomalies but results in a significantly increased rate of PTL. In Aim 1, we will analyze effector and regulatory T cell activation in mice in the context of two pregnancy complications: fetal intervention and intrauterine infection. In Aim 2, we will examine maternal immune responses against fetal and placental antigens in patients with PTL using a novel functional assay to track allospecific T cells and explore changes in tolerance mechanisms that may be perturbed during inflammation. In Aim 3, we will examine fetal T cell responses in patients with PTL to understand the mechanisms of accelerated T cell maturation in this population. Our short-term goal is to understand the possible contribution of maternal and fetal T cells to the pathogenesis of PTL. Our long-term goals are to understand mechanisms leading to term and preterm labor, to gain insights into fetal and neonatal T cell development and its consequences for neonatal health, and, ultimately, to develop targeted therapies to impede T cell activation in patients at risk for PTL.

 描述（由申请人提供）：早产（定义为妊娠37周前分娩）是发达国家新生儿发病率和死亡率的最重要原因，其发病率持续上升。目前的治疗效果有限，因为导致分娩的基本机制-无论是足月还是早产-都不清楚。由于成功的怀孕取决于母亲和胎儿之间的多层耐受性，妊娠并发症可能涉及这些机制的崩溃。我们建议检查新的假设，感染或炎症在怀孕期间的结果在激活的母体T细胞特异性胎儿或胎盘抗原，和胎儿T细胞特异性母体抗原，最终导致排斥反应和早产。我们将使用小鼠模型和患者样本来验证这一假设。在我们的小鼠模型中，我们先前已经表明，胎儿干预（一种无菌炎症模型）激活了母体T细胞， 特异于胎儿抗原，并且这种激活可导致同种异体胎儿的选择性死亡。这一发现与李斯特菌感染期间怀孕小鼠T细胞活化和胎儿丢失的其他报告一致。我们现在将使用一种新型Nur 77-Foxp 3双报告小鼠来描述这些发现的细胞机制，该小鼠跟踪效应T细胞和调节T细胞中的T细胞受体参与。在我们的患者样本中，我们已经开发了强大的测定来计数同种异体特异性T细胞，以检查它们对临床早产（PTL）的可能贡献。我们令人惊讶地发现，母体血液中的T细胞增殖在怀孕期间是钝化的，但胎儿（脐带血）T细胞在继发于感染的PTL患者中被激活。我们建议检查是否与胎盘（蜕膜）接触的母体组织层中的母体T细胞在PTL期间被激活，以及导致继发于感染或胎儿干预的PTL患者中胎儿T细胞早期激活的机制。后者通常在我们的机构进行，以治疗胎儿先天性异常，但结果在显着增加PTL率。在目标1中，我们将分析小鼠在两种妊娠并发症（胎儿干预和宫内感染）背景下的效应和调节T细胞活化。在目标2中，我们将使用一种新的功能测定法来跟踪同种异体特异性T细胞，并探索炎症期间可能受到干扰的耐受机制的变化，以检查PTL患者对胎儿和胎盘抗原的母体免疫应答。在目标3中，我们将检查PTL患者的胎儿T细胞反应，以了解该人群中T细胞加速成熟的机制。我们的短期目标是了解母体和胎儿T细胞对PTL发病机制的可能贡献。我们的长期目标是了解导致足月和早产的机制，深入了解胎儿和新生儿T细胞发育及其对新生儿健康的影响，并最终开发靶向治疗方法，以阻止PTL风险患者的T细胞活化。