Complement as a Mediator of Recurrent Miscarriages

描述（由申请人提供）：1%至3%的美国。S.妇女经常流产。虽然大多数妇女反复流产的原因尚不清楚，但已经提出了一种免疫机制，涉及母亲免疫系统对孕体的不适当和有害的识别。我们最近在小鼠模型中开发的数据表明先天免疫机制会引发堕胎。具体来说，我们已经确定了一个新的作用，补体激活作为一个早期效应的途径，导致妊娠损失与胎盘炎症。我们的工作表明，补体激活是抗磷脂抗体诱导的妊娠丢失和胎儿生长受限的核心机制，并且补体激活是TNF-α增加所必需的，并且先于TNF-α增加。在本申请中，我们将检验补体激活是免疫介导的流产小鼠模型中胎儿丢失发病机制中的必要中间事件的假设，所述免疫介导的流产代表围着床期和着床后丢失。我们的总体目标是阐明介导复发性自然流产的补体途径，并确定预防复发性流产的干预措施的目标。因此，我们的目标是： 目标1。目的探讨补体在DBA/2交配雌性CBA/J小鼠自然流产模型中的作用。(a)为了确定C3沉积与（B）使用补体缺陷小鼠和特异性补体抑制剂鉴定启动补体激活并导致C3沉积在蜕膜中的途径;（c）确定蜕膜中是否出现鼠补体调节蛋白表达减少的情况，以及是否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）确定胎儿损失的哪些细胞和细胞因子介导物导致蜕膜中有害的补体激活。 目标2.确定补体在DBA/2交配的TNF-α处理的雌性C57 BL/6模型中胎儿丢失中的作用，并鉴定介导体内组织损伤和胎儿丢失的特异性补体激活产物。(a)确定C3是否沉积在蜕膜内;流产是否需要C3活化;以及TNF-α处理、C3沉积和细胞浸润之间的关系;（B）使用补体缺陷小鼠和特异性补体抑制剂来确定有助于马槟榔碱依赖性流产的补体组分或受体 如果补体激活是反复妊娠丢失的必要机制，阐明特定补体成分的作用将为开发新疗法提供基础，为选择其中的一个理由，以及改善患者结局的能力。此外，我们的研究将提供深入了解补体诱导疾病的机制，并提出预防，逮捕或修改补体介导的炎症性疾病的方法。

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.