NETs as therapeutic targets in obstetric APS

项目概要/摘要 患有抗磷脂综合征 (APS) 自身免疫性疾病的孕妇会出现 晚期死产、宫内生长受限和严重先兆子痫的风险显着增加。尽管 我们在诊所治疗产科 APS 方面取得了一些进展，包括常规服用阿司匹林 和肝素——前瞻性研究发现，大约八分之一的 APS 妊娠仍会以胎儿告终 灭亡。血栓形成实际上是 APS 胎盘组织病理学的一个罕见特征；相反，常见的异常 包括补体分裂产物的沉积、蜕膜中性粒细胞的大量募集以及不足 绒毛外滋养细胞的组织重塑。事实上，我们小组之前检测到中性粒细胞胞外 人类 APS 胎盘绒毛间隙中的陷阱 (NET)，它们可能会破坏正常的滋养层 功能。 NET 是由染色质和杀菌蛋白组成的蜘蛛网状缠结，从激活的细胞中排出。 中性粒细胞通过“NETosis”。我们之前发现抗磷脂抗体（aPL）介导的 NETosis 是 APS 模型中血栓形成所必需的，并且已经确定了一些可以帮助的药理学策略 恢复中性粒细胞稳态（包括秋水仙碱、腺苷受体激动剂、选择素配体抑制剂、 甚至天然补充剂，如生姜）。如果将这种方法扩展到 APS 相关的产科发病率？我们认为迫切需要回答这个问题。 新数据表明 NETosis 阻断可以保护 APS 小鼠免于胎儿流产，这一假设 推动这一提议的是 NETosis 抑制剂，如秋水仙碱或双嘧达莫，可以在我们的研究中找到一席之地。 临床上作为辅助治疗。虽然这项研究的颠覆性假设意味着它并非没有风险，但回报 希望有足够的临床前数据来支持秋水仙碱等药物的临床试验——该药物已经在 根据其在家族性地中海热中的常规使用，已知其在怀孕期间具有良好的安全性。 目标 1 将阐明 NETosis 可能促进 aPL 介导的产科的机制 发病率。成功完成该目标将确定 (i) 最有可能是产科 APS 患者衍生的 aPL 触发 NETosis，(ii) NET 在放大 aPL 介导的滋养层功能障碍中的作用，以及 (iii) 是否 阻断 NETosis 可降低 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。成功完成这一转化目标是 预计将进一步阐明 NET 在 aPL 介导的产科发病率中的作用，同时可能确定 值得临床紧急评估的新疗法。

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.