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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

基本信息

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
项目类别：
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

项目摘要

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 周之前分娩）是发达国家新生儿发病和死亡的最重要原因，且其发病率持续上升。目前的治疗方法效果有限，因为导致分娩的基本机制（无论是足月还是早产）尚不清楚。由于成功怀孕取决于母亲和胎儿之间的多层次耐受性，因此妊娠并发症可能涉及这种机制的崩溃。我们建议检验新的假设，即妊娠期间的感染或炎症会导致胎儿或胎盘抗原特异性的母体 T 细胞以及母体抗原特异性的胎儿 T 细胞激活，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检验这一假设。在我们的小鼠模型中，我们之前已经证明胎儿干预（无菌炎症模型）会激活母体 T 细胞，这些细胞对胎儿抗原具有特异性，并且这种激活可以导致同种异体胎儿的选择性死亡。这一发现与怀孕小鼠李斯特菌感染期间 T 细胞激活和胎儿丢失的其他报道一致。现在，我们将使用新型 Nur77-Foxp3 双报告小鼠来描述这些发现的细胞机制，该小鼠可追踪效应 T 细胞和调节性 T 细胞中 T 细胞受体的参与。在我们的患者样本中，我们开发了强大的检测方法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。我们惊奇地发现，妊娠期间母血中的 T 细胞增殖减弱，但继发于感染的 PTL 患者中胎儿（脐带血）T 细胞被激活。我们建议检查继发于感染或胎儿干预的 PTL 患者中与胎盘（蜕膜）接触的母体组织层中的母体 T 细胞在 PTL 期间是否被激活，以及导致胎儿 T 细胞早期激活的机制。后者通常在我们的机构中用于治疗先天性异常的胎儿，但会导致 PTL 发生率显着增加。在目标 1 中，我们将在两种妊娠并发症（胎儿干预和宫内感染）的背景下分析小鼠中效应和调节性 T 细胞的激活。在目标 2 中，我们将使用一种新的功能测定来检测 PTL 患者针对胎儿和胎盘抗原的母体免疫反应，以追踪同种异体特异性 T 细胞，并探索炎症期间可能受到干扰的耐受机制的变化。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，并最终开发靶向疗法来阻止有 PTL 风险的患者的 T 细胞激活。