Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis
Identification of a Monoclonal Antibody That Attenuates Antiphospholipid Syndrome-Related Pregnancy Complications and Thrombosis
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DOI：
10.1371/journal.pone.0158757
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发表时间：
2016-07-27
期刊：
影响因子：
3.7
通讯作者：
Shaul, Philip W.
中科院分区：
文献类型：
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作者：
Mineo, Chieko;Lanier, Lane;Shaul, Philip W.
在抗磷脂综合征（APS）中，患者产生抗磷脂抗体（aPL），促进血栓形成和不良妊娠结局。目前的抗凝治疗仅部分有效，并伴有多种并发症。我们之前发现，aPL对细胞表面β 2-糖蛋白I （β 2- gpi）的识别在内皮细胞和胎盘滋养层细胞中启动载脂蛋白E受体2 （apoER2）依赖的信号传导，最终分别促进血栓形成和胎儿丢失。在这里，我们试图鉴定一种针对β 2-GPI的单克隆抗体（mAb），该抗体可以在小鼠细胞培养和APS疾病终点中抑制apl诱导的过程。在对培养内皮细胞内皮NO合成酶（eNOS）活性的筛选中，我们发现aPL抑制eNOS，而mAb 1N11不抑制eNOS，相反，1N11阻止aPL的作用。共免疫沉淀研究表明，1N11降低了β 2-GPI的致病抗体结合，并阻断了apl诱导的β 2-GPI与apoER2之间的复合物形成。1N11还能阻止aPL对内皮细胞迁移的拮抗作用，并在小鼠中逆转aPL引起的再内皮化损伤，这是由致病抗体引起的非血栓性血管闭塞的基础。此外，aPL对滋养细胞增殖和迁移的抑制作用被1N11否定，并且1N11可以阻止aPL引起的妊娠小鼠胎儿吸收增加6倍以上的现象。此外，aPL对血栓形成的促进作用被1N11否定。因此，1N11已被确定为一种减轻小鼠aps相关妊娠并发症和血栓形成的单抗。1N11可能提供一种有效的、基于机制的治疗方法，以对抗APS患者经常遭受的毁灭性疾病。
In the antiphospholipid syndrome (APS), patients produce antiphospholipid antibodies (aPL) that promote thrombosis and adverse pregnancy outcomes. Current therapy with anticoagulation is only partially effective and associated withmultiple complications. We previously discovered that aPL recognition of cell surface beta 2-glycoprotein I (beta 2-GPI) initiates apolipoprotein E receptor 2 (apoER2)-dependent signaling in endothelial cells and in placental trophoblasts that ultimately promotes thrombosis and fetal loss, respectively. Here we sought to identify a monoclonal antibody (mAb) to beta 2-GPI that negates aPL-induced processes in cell culture and APS disease endpoints in mice. In a screen measuring endothelial NO synthase (eNOS) activity in cultured endothelial cells, we found that whereas aPL inhibit eNOS, the mAb 1N11 does not, and instead 1N11 prevents aPL action. Coimmunoprecipitation studies revealed that 1N11 decreases pathogenic antibody binding to beta 2-GPI, and it blocks aPL-induced complex formation between beta 2-GPI and apoER2. 1N11 also prevents aPL antagonism of endothelial cell migration, and in mice it reverses the impairment in reendothelialization caused by aPL, which underlies the non-thrombotic vascular occlusion provoked by disease-causing antibodies. In addition, aPL inhibition of trophoblast proliferation and migration is negated by 1N11, and the more than 6-fold increase in fetal resorption caused by aPL in pregnant mice is prevented by 1N11. Furthermore, the promotion of thrombosis by aPL is negated by 1N11. Thus, 1N11 has been identified as an mAb that attenuates APS-related pregnancy complications and thrombosis in mice. 1N11 may provide an efficacious, mechanism-based therapy to combat the often devastating conditions suffered by APS patients.