Mechanisms of aPL antibody-induced pregnancy loss

aPL抗体引起流产的机制

• 批准号: 6975582
• 负责人: Jane E Salmon
• 金额: $ 10万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-22 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6975582
• 关键词: antibody receptor; antiphospholipid syndrome; complement pathway regulation; complement receptor; cytokine; decidua; disease /disorder model; inflammation; laboratory mouse; pathologic process; prenatal growth disorder

DESCRIPTION (provided by applicant): The antiphospholipid syndrome (APS), characterized by thrombosis and pregnancy loss that occurs in the presence of antiphospholipid (aPL) antibodies, is a leading cause of miscarriage and maternal and fetal morbidity. Pregnancy complications in women with APS include fetal death, preeclampsia, and intrauterine growth restriction (IUGR). The pathogenic mechanisms that lead to injury in vivo are incompletely understood and the therapy for pregnant women with APS is only partially successful. Our studies in a murine model of APS, induced by passive transfer of human Apl antibodies, indicate that complement activation plays an essential and causative role in fetal loss and growth restriction. In addition, treatment with heparin, the standard therapy for pregnant patients with APS, prevents complement activation and protects mice from pregnancy complications induced by aPL antibodies, while anticoagulants that do not inhibit complement do not protect pregnancies. These studies indicate that APS is an inflammatory disease and, they suggest that complement inhibitory therapy might be an effective treatment. Our overall goals are to use the murine model of APS to determine how complement is activated, which complement products mediate the clinical complications associated with aPL antibodies, and the relative role of complement activation within the overall inflammatory cascade. In addition, we propose to test the hypothesis that activation of complement at the maternal-fetal interface plays an etiologic role in IUGR. Accordingly, our aims are: Aim 1. To determine which complement components and receptors are necessary or sufficient to mediate aPL antibody-induced placental injury, fetal loss and/or IUGR. (a) To identify the pathways that initiate complement activation and lead(s) to complement deposition in deciduas and poor pregnancy outcomes; (b) To identify the complement activation products and receptors that mediate fetal injury; (c) To assess the role of murine complement regulatory proteins in the control of local complement activation. Aim 2. To define the role of aPL antibody-mediated complement activation within the overall inflammatory cascade in order to identify complement-dependent vs. complement-independent mechanisms, (a) To define the contribution of Fc?R to aPL antibody-mediated injury; (b) To define the cellular and cytokine mediators which contribute to complement activation in deciduas, to IUGR and to fetal loss. The proposed study, together with our ongoing work to define the role of complement and cytokines in pregnancy complications in APS patients, will provide insights into the mechanisms by which complement induces disease and define targets for interventions to prevent aPL antibody-associated fetal demise and IUGR. Additionally, understanding how aPL antibodies "cause" pregnancy loss may translate into new concepts about maternal-fetal tolerance and miscarriages in general and benefit women with non-aPL-related pregnancy complications.

描述（由申请人提供）： 抗磷脂综合征（APS），其特征在于血栓形成和妊娠丢失，发生在抗磷脂（aPL）抗体的存在下，是流产和母亲和胎儿发病的主要原因。APS妇女的妊娠并发症包括胎儿死亡、先兆子痫和宫内生长受限（IUGR）。导致体内损伤的致病机制尚不完全清楚，对妊娠期APS的治疗仅部分成功。我们的研究表明，在小鼠模型的APS，诱导被动转移的人Apl抗体，补体激活起着重要的作用，胎儿损失和生长受限的原因。此外，肝素治疗（APS妊娠患者的标准治疗）可防止补体激活并保护小鼠免受aPL抗体诱导的妊娠并发症，而不抑制补体的抗凝剂不能保护妊娠。这些研究表明，APS是一种炎症性疾病，他们认为补体抑制疗法可能是一种有效的治疗方法。我们的总体目标是使用APS的小鼠模型来确定补体是如何被激活的，哪些补体产物介导与aPL抗体相关的临床并发症，以及补体激活在总体炎症级联中的相对作用。此外，我们建议测试的假设，在母胎界面的补体激活起着病因的作用，在IUGR。因此，我们的目标是： 目标1.确定哪些补体成分和受体是介导aPL抗体诱导的胎盘损伤、胎儿丢失和/或IUGR所必需或充分的。(a)确定启动补体激活并导致蜕膜中补体沉积和不良妊娠结局的途径;（B）确定介导胎儿损伤的补体激活产物和受体;（c）评估鼠补体调节蛋白在控制局部补体激活中的作用。 目标二。为了确定aPL抗体介导的补体激活在整个炎症级联反应中的作用，以确定补体依赖性与补体非依赖性机制，（a）为了确定Fc？（B）确定有助于蜕膜中补体激活、IUGR和胎儿丢失的细胞和细胞因子介质。 这项拟议的研究，以及我们正在进行的工作，以确定补体和细胞因子在APS患者妊娠并发症中的作用，将提供补体诱导疾病的机制的见解，并确定干预措施的目标，以防止aPL抗体相关的胎儿死亡和IUGR。此外，了解aPL抗体如何“导致”妊娠丢失可能会转化为关于母胎耐受和流产的新概念，并使患有非aPL相关妊娠并发症的女性受益。