NETs as therapeutic targets in obstetric APS

项目概要/摘要 患有自身免疫性疾病的孕妇称为抗磷脂综合征（APS）， 晚期死产、宫内生长受限和重度先兆子痫的风险显著增加。尽管 我们在临床上如何治疗产科APS方面取得了一些进展，包括常规服用阿司匹林 前瞻性研究发现，大约八分之一的APS妊娠仍将以胎儿死亡结束。 死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， 包括补体分裂产物沉积、蜕膜中性粒细胞募集旺盛以及不充分 绒毛外滋养层组织重塑。事实上，我们的小组以前检测到中性粒细胞外 在人类APS胎盘的绒毛间隙中，它们可能破坏正常的滋养层细胞 功能协调发展的NET是由染色质和杀微生物蛋白质组成的蜘蛛网状缠结， 中性粒细胞通过"NETosis"。我们以前发现抗磷脂抗体（aPL）介导的NETosis是 在APS模型中血栓形成所需的药物，并确定了一些药理学策略， 恢复中性粒细胞的体内平衡（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。 新的数据表明NETosis阻断可保护APS小鼠免于胎儿丢失， 引导这一建议的是，NETosis抑制剂，如秋水仙碱或潘生丁可以找到一个地方，在我们的 作为辅助治疗。虽然这项研究的破坏性假设意味着它并非没有风险，但回报 将有希望获得足够的临床前数据来支持秋水仙碱等药物的临床试验， 根据其在家族性地中海热中的常规使用，已知其在妊娠期具有良好的安全性。 目的1将阐明NETosis可能有助于APL介导的产科疾病的机制。 发病率。成功完成这一目标将确定（i）最有可能的产科APS患者源性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降低小鼠中APL介导的产科发病率。 目的2将确定给予秋水仙碱和/或腺苷受体激动剂 减轻小鼠中aPL介导的产科发病率。成功地完成这一翻译目标是 预计将进一步阐明NET在APL介导的产科发病率中的作用，同时可能识别 新的治疗方法，值得在临床上进行紧急评估。

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.