NETs as therapeutic targets in obstetric APS

项目摘要/摘要 患有抗磷脂综合征(APS)的自身免疫性疾病的孕妇有 显著增加晚期死产、宫内生长受限和严重先兆子痫的风险。尽管 我们在临床治疗产科APS方面的一些进展--包括常规服用阿司匹林 而肝素-前瞻性研究发现，大约八分之一的APS妊娠仍将以胎儿结束。 死亡。血栓形成实际上是APS胎盘组织病理学的罕见特征；相反，常见的异常 包括补体裂解产物沉积、蜕膜中性粒细胞募集旺盛和不足 绒毛外滋养细胞的组织重塑。事实上，我们的小组之前检测到中性粒细胞胞外 人APS胎盘绒毛间隙中的陷阱(Net)，在那里它们可能扰乱正常滋养细胞 功能。Net是由染色质和从活性物质中排出的杀微生物活性蛋白组成的蜘蛛网状缠结 中性粒细胞通过“网织”。我们先前已经发现抗磷脂抗体(APL)介导的NETsis是 在APS模型中血栓形成所需的-并且已经确定了一些可以帮助 恢复中性粒细胞动态平衡(包括秋水仙碱、腺苷受体激动剂、选择素配体抑制剂、 甚至是生姜等天然补充剂)。如果将这些方法推广到 APS相关的产科发病率？我们认为迫切需要回答这个问题。 在新数据的支持下，NETsis阻断可以保护APS小鼠免受胎儿损失，这一假设得到了支持 这项提议的领头羊是NETase抑制剂，如秋水仙碱或双嘧达莫，可以在我们的 诊所作为辅助疗法。虽然这项研究的颠覆性假设意味着它并不是没有风险，但回报是 将有望有足够的临床前数据来支持像秋水仙碱这样的药物的临床试验--这种药物已经 已知在怀孕期间具有良好的安全性，这是基于其在家族性地中海热中的常规使用。 目标1将阐明NETsis在APL介导的产科疾病中的作用机制 发病率。这一目标的成功完成将确定(I)最有可能由产科APS患者衍生的APL (Ii)Net在放大APL介导的滋养层功能障碍中的作用，以及(Iii)Net是否 阻断NETsis可减少APL介导的小鼠产科发病率。 目标2将确定给予秋水仙碱和/或腺苷受体激动剂的程度 减轻APL介导的小鼠产科发病率。成功完成这一翻译目标是 期望进一步阐明Net在APL介导的产科发病率中的作用，同时潜在地确定 值得在临床上进行紧急评估的新疗法。

PROJECT SUMMARY/ABSTRACT Pregnant individuals with the autoimmune disease known as antiphospholipid syndrome (APS) have a markedly increased risk of late-term stillbirth, intrauterine growth restriction, and severe preeclampsia. Despite some progress as to how we treat obstetric APS in our clinics—including the routine administration of aspirin and heparins—prospective studies have found that roughly 1 in 8 APS pregnancies will still end with fetal demise. Thrombosis is actually a rare feature of APS placental histopathology; instead, common abnormalities include deposition of complement split products, exuberant decidual neutrophil recruitment, and inadequate tissue remodeling by extravillous trophoblasts. Indeed, our group previously detected neutrophil extracellular traps (NETs) in the intervillous space of human APS placentae, where they may disrupt normal trophoblast functions. NETs are spider web-like tangles of chromatin and microbicidal proteins expelled from activated neutrophils via “NETosis.” We have previously found that antiphospholipid antibody (aPL)-mediated NETosis is required for thrombosis in models of APS—and have identified some pharmacologic strategies that can help restore neutrophil homeostasis (including colchicine, adenosine receptor agonists, selectin ligand inhibitors, and even natural supplements such as ginger). Would such approaches prove valuable if extended to APS-associated obstetric morbidity? We believe there is an urgent need to answer this question. Bolstered by new data indicating that NETosis blockade protects APS mice from fetal loss, the hypothesis shepherding this proposal is that NETosis inhibitors such as colchicine or dipyridamole could find a place in our clinics as adjuvants therapies. While this study's disruptive hypothesis means it is not without risk, the reward will hopefully be sufficient preclinical data to support a clinical trial of a drug like colchicine—which is already known to have a good safety profile in pregnancy based on its routine use in Familial Mediterranean Fever. Aim 1 will elucidate mechanisms by which NETosis may contribute to aPL-mediated obstetric morbidity. Successful completion of this Aim will identify (i) the obstetric APS patient-derived aPL most likely to trigger NETosis, (ii) the role of NETs in amplifying aPL-mediated trophoblast dysfunction, and (iii) whether blocking NETosis reduces aPL-mediated obstetric morbidity in mice. Aim 2 will determine the extent to which administering colchicine and/or adenosine receptor agonists mitigates aPL-mediated obstetric morbidity in mice. Successful completion of this translational Aim is expected to further elucidate the role of NETs in aPL-mediated obstetric morbidity, while potentially identifying new therapies that merit urgent evaluation in the clinic.