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：
9280814
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/9280814
关键词：
37 weeks gestation Adaptive Immune System African American Alloantigen 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 FOXP3 gene Failure Fetal Distress Fetus Financial cost Future General Population Goals Health Health Care Costs Human Immune response Immune system Immunologics Incidence Infant Mortality Infection Inflammation Inflammatory Innate Immune Response Innate Immune System 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 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 experimental study fetal fetal inflammatory response syndrome fetus surgery insight mouse model neonatal morbidity novel novel therapeutics pregnant premature prevent public health relevance 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，其发病率持续上升，因为导致其的基本机制有限。由于成功妊娠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，我们建议检查新的假设，即妊娠期间的感染或炎症。妊娠导致对胎儿或胎盘抗原特异性的母体 T 细胞以及对母体抗原特异性的胎儿 T 细胞的激活，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在小鼠中检验这一假设。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，这些细胞特异性针对胎儿抗原，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，我们现在将使用一种新的方法来描述这些发现的细胞机制。 Nur77-Foxp3 双报告小鼠可追踪效应 T 细胞和调节 T 细胞中 T 细胞受体的参与情况。在我们的患者样本中，我们开发了强大的检测方法来枚举同种异体 T 细胞，以检查它们对临床早产的可能贡献。 (PTL)。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减弱，但胎儿（脐带血）T 细胞在 PTL 继发感染的患者中被激活。在继发于感染或胎儿干预的 PTL 患者中，与胎盘（蜕膜）接触的组织层在 PTL 期间被激活，以及导致胎儿 T 细胞早期激活的机制。后者通常在我们机构进行以治疗胎儿。有先天性的异常，但导致 PTL 率显着增加。在目标 1 中，我们将分析两种妊娠并发症（胎儿干预和宫内感染）下小鼠的效应细胞和调节性 T 细胞激活。在目标 2 中，我们将检查母体免疫反应。使用一种新的功能测定来追踪 PTL 患者的胎儿和胎盘抗原，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。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。分娩，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以阻止有 PTL 风险的患者的 T 细胞激活。