Complement as a Mediator of Recurrent Miscarriages

补充作为复发性流产的调解者

• 批准号: 6834641
• 负责人: Jane E Salmon
• 金额: $ 35.5万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-15 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6834641
• 关键词: complement; decidua; embryo /fetus death; genetically modified animals; immunity; immunocytochemistry; inflammation; laboratory mouse; northern blottings; polymerase chain reaction; pregnancy loss; spontaneous abortion; tumor necrosis factor alpha; western blottings

DESCRIPTION (provided by applicant): Between 1% and 3% of U. S. women suffer recurrent miscarriages. Although the cause of recurrent miscarriages in most women is unknown, an immune mechanism involving inappropriate and injurious recognition of the conceptus by the mother's immune system has been proposed. We have recently developed data in murine models indicating that innate immune mechanisms trigger abortion. Specifically, we have identified a novel role for complement activation as an early effector in the pathway leading to pregnancy loss associated with placental inflammation. Our work shows that complement activation is a central mechanism contributing to antiphospholipid antibody-induced pregnancy loss and fetal growth restriction and that complement activation is required for and precedes increases in TNF-alpha. In this application, we will test the hypothesis that complement activation is a necessary intermediary event in the pathogenesis of fetal loss in murine models of immunologically-mediated abortion representing both peri-implantation and postimplantation loss. Our overall goals are to elucidate the complement pathways that mediate recurrent spontaneous abortion and to define targets for interventions to prevent recurrent human miscarriage. Accordingly, our aims are: Aim 1. To define the role of complement in fetal loss in the DBA/2-mated female CBA/J murine model of spontaneous abortion. (a) To determine the temporal relationships between deposition of C3 (and of other complement components) and infiltration of inflammatory cells and production of TNF-q within decidua; (b) To identify the pathway(s) that initiate(s) complement activation and lead to C3 deposition in the decidua using complement deficient mice and specific complement inhibitors; (c) To determine whether diminished expression of murine complement regulatory proteins occurs in decidua and contributes to local complement activation; (d) To identify the complement pathway activation products and receptors that mediate fetal injury; (e) To determine which cellular and cytokine mediators of fetal loss contribute to deleterious complement activation in the deciduas. Aim 2. To define the role of complement in fetal loss in the DBA/2-mated TNF-a-treated female C57BL/6 model and to identify the specific complement activation products that mediate in vivo tissue injury and fetal loss. (a) To determine whether C3 is deposited within deciduas; whether C3 activation is required for abortion; and the relationship between TNF-alpha treatment, C3 deposition, and cellular infiltration; (b) To define the complement components or receptors that contribute to cytokine-dependent abortion using complement deficient mice and specific complement inhibitors If complement activation is a necessary mechanism in repeated pregnancy loss, elucidating the roles of specific complement components will provide a basis for developing new therapies, a rationale for choosing among them, and the capacity to improve patient outcomes. In addition, our studies will provide insights into mechanisms by which complement-induces disease and suggest means to prevent, arrest, or modify complement-mediated inflammatory disorders.

描述（由申请人提供）：1％至3％的美国妇女遭受反复流产。尽管大多数女性在大多数妇女中的反复流产的原因是未知的，但已经提出了涉及母亲免疫系统对这一概念的不适当和有害认识的免疫机制。我们最近在鼠模型中开发了数据，表明先天免疫机制触发流产。具体而言，我们已经确定了补体激活的新作用是导致胎盘炎症妊娠丧失的途径中的早期效应子。我们的工作表明，补体激活是一种促进抗磷脂抗体诱导的妊娠丧失和胎儿生长限制的中心机制，并且需要补体激活，并且在TNF-alpha中增加了补体。在此应用中，我们将测试以下假设：补体激活是胎儿丧失的发病机理中必要的中间事件，在免疫学介导的流产的鼠模型中，代表植入植入术和植入后丧失。我们的总体目标是阐明介导复发自发流产的补体途径，并定义干预措施以防止复发人类流产的目标。因此，我们的目标是： 目的1。定义补体在DBA/2伴侣的雌性CBA/J鼠自发流产模型中的作用。 （a）确定C3的沉积（以及其他补体成分）与炎症细胞的浸润与Decidua内TNF-Q的产生之间的时间关系； （b）使用补体缺乏小鼠和特定的补体抑制剂来确定启动启动（s）补体激活并导致C3沉积的途径； （c）确定鼠补体调节蛋白的表达降低是否发生在Decidua中，并有助于局部补体激活； （d）确定介导胎儿损伤的补体途径激活产物和受体； （e）确定胎儿丧失的细胞和细胞因子介质有助于deciDUAS中的有害补体激活。 目的2。定义补体在DBA/2-MET-MET TNF-A处理的雌性C57BL/6模型中的作用，并确定在体内组织损伤和胎儿损失中介导的特定补体激活产物。 （a）确定C3是否沉积在Deciduas中；堕胎是否需要C3激活；以及TNF-α治疗，C3沉积和细胞浸润之间的关系； （b）定义使用补体缺乏小鼠和特定补体抑制剂导致细胞因子依赖性流产的补体成分或受体 如果补体激活是反复怀孕丧失的必要机制，则阐明特定补体成分的作用将为开发新疗法，选择的基本原理以及改善患者预后的能力提供基础。此外，我们的研究将提供有关补体诱导疾病的机制的见解，并提出了预防，逮捕或修改补体介导的炎症性疾病的方法。