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（由适用提供）：早产（妊娠37周之前定义为分娩）是发达国家新生儿发病率和死亡率的最重要原因，其事件持续上升。目前的处理效率有限，因为导致劳动世界价值或早产的基本机制尚不清楚。由于成功怀孕取决于母亲与胎儿之间的多层公差，因此妊娠并发症可能涉及这种机制的破裂。我们建议研究新的假设，即怀孕期间的感染或感染会导致特异性的胎儿或斑点抗原特有的母体T细胞激活，以及针对母体抗原特异的胎儿T细胞的激活，最终导致排斥和早产。我们将使用小鼠模型和患者样品来检验此假设。在我们的小鼠模型中，我们先前已经表明，胎儿干预（一种无菌注射模型）激活了材料T细胞针对胎儿抗原的特异性，这种激活可能会导致同种异体胎儿的选择性灭亡。这一发现与怀孕小鼠李斯特菌感染期间T细胞激活和胎儿丧失的其他报道一致。现在，我们将使用一种新型的NUR77-FOXP3双报告小鼠来描述这些发现的细胞机制，该小鼠在效应子和调节性T细胞中均跟踪T细胞受体参与度。在我们的患者样本中，我们开发了强大的暗杀性，以列举高特异性T细胞，以检查其对临床早产（PTL）的可能贡献。我们惊讶地发现，在怀孕期间，孕产妇血液中的T细胞增殖会钝化，但继发于感染的PTL患者中，该胎儿（脐带血）T细胞被激活。我们提出要检查在PTL期间与Plapeta接触（DeciDua）接触的母体组织层中的Mater T细胞是否在PTL感染或胎儿干预的PTL患者中激活了胎儿T细胞的早期激活。后者通常在我们的机构中进行先天异常治疗胎儿，但会导致PTL率显着提高。在AIM 1中，我们将在两种妊娠并发症的背景下分析小鼠的效应子和调节性T细胞的激活：胎儿干预和插入式感染。在AIM 2中，我们将使用一种新型的功能测定法检查PTL患者对胎儿和斑点抗原的材料免疫反应，以跟踪同种T细胞，并探索在炎症期间可能会受到干扰的耐受性机制的变化。在AIM 3中，我们将检查PTL患者的胎儿T细胞反应，以了解该人群加速T细胞成熟的机制。我们的短期目标是了解母体和胎儿T细胞对PTL发病机理的可能贡献。我们的长期目标是了解导致术语和早产劳动的机制，以了解对胎儿和新生儿T细胞发育及其对新生儿健康的后果，并最终开发有针对性的疗法来阻碍患有PTL风险的患者的T细胞激活。