Anti-inflammatory drug target to reduce adverse pregnancy outcomes.

摘要 子宫内感染/炎症（IUI）是导致早产和胎儿炎症的主要因素， 胎儿器官如脑、肺和胃肠道的损伤反应。然而，机制和 精确的治疗方法仍然难以捉摸，主要是因为缺乏相关的动物模型。我们有 在早产恒河猴中开发了一种强大的宫内感染新模型：羊膜内（IA） 肝E.大肠杆菌感染后24 h开始加用抗生素。这种模式导致持久的IUI。重要的是 尽管E.大肠杆菌菌血症，导致早产 (PTL)胎儿免疫异常和胎儿神经炎症。我们现在建议验证IL 1作为药物靶点 用于IUI引起的早产和胎儿炎症。这项拨款是基于我们的数据，阿那白滞素（IL 1受体 临床上用于类风湿性关节炎的拮抗剂）显著降低了 母胎界面和羊水IL 6、PGE 2在不同但广泛使用的IA LPS模型中。 此外，阿那白滞素逆转了胎儿脾脏中LPS诱导的“炎性Treg”。我们建议测试 假设阿那白滞素将减少感染模型中残留的母体和胎儿炎症， 在孕妇中密切模拟IUI，具有两个目的。在目标1中，我们将询问抗IL 1是否定向抗- 炎症治疗可减少宫内感染引起的炎症和早产。我们将使用 最先进的单细胞转录组学方法，以解开细胞和分子机制， 母胎界面的炎症，定义了对IL 1有反应的IUI的分娩相关途径 抑制作用使用多参数流式细胞术，我们将确定中性粒细胞募集的机制， 绒毛膜-蜕膜中的激活。在目标2中，我们将确定粘膜和全身胎儿免疫扰动 暂时性菌血症和不育胎儿炎症引起的我们将确定阿那白滞素是否能减少 IUI引起的胎儿全身炎症和神经炎症。这些研究将发展关键的 未来研究的知识基础，旨在重新利用阿那白滞素作为一种新的抗炎治疗， 人类IUI。一个多学科协作团队将使用高分辨率免疫学、基因组学/蛋白质组学， 神经科学，以及在动物模型中模拟IUI和胎儿炎症的转化方法， 与人类的病理学非常相似

Abstract Intrauterine infection/inflammation (IUI) is a major contributor to preterm labor and fetal inflammation leading to injury responses in fetal organs such as the brain, lung and the GI tract. However, the mechanisms and precise therapeutic approaches remain elusive largely because of lack of relevant animal models. We have developed a powerful new model of intrauterine infection in preterm Rhesus macaques: Intraamniotic (IA) injection of live E. coli followed 24h later with antibiotics. This model results in persistent IUI. Importantly, the maternal and fetal inflammation persists despite clearance of E. coli bacteremia, resulting in preterm labor (PTL), fetal immune aberrations and fetal neuroinflammation. We now propose validating IL1 as a drug target for IUI induced prematurity and fetal inflammation. This grant is based on our data that Anakinra (IL1 receptor antagonist used clinically for rheumatoid arthritis) significantly decreased neutrophilic infiltration at the maternal-fetal interface and amniotic fluid IL6, PGE2 in a different but widely used model of IA LPS. Furthermore, Anakinra reversed the LPS-induced “inflammatory Treg” in the fetal spleen. We propose to test the hypothesis that Anakinra will reduce the residual maternal and fetal inflammation in infectious models that closely simulate IUI in pregnant women with two Aims. In Aim 1, we will ask if anti IL1 directed anti- inflammatory therapy will decrease intrauterine infection induced inflammation and preterm labor. We will use state-of-the-art single-cell transcriptomic approach to unravel cellular and molecular mechanisms of inflammation at the maternal-fetal interface, define labor associated pathways of IUI that are responsive to IL1 inhibition. Using multi-parameter flow cytometry, we will identify mechanisms of neutrophil recruitment and activation in the chorio-decidua. In Aim 2, We will identify mucosal and systemic fetal immune perturbations resulting from transient bacteremia and sterile fetal inflammation. We will determine if Anakinra can reduce fetal systemic inflammation and neuroinflammation resulting from IUI. These studies will develop the critical knowledge base for future studies aimed at repurposing of Anakinra as a novel anti-inflammatory therapy for human IUI. A collaborative multi-disciplinary team will use high-resolution immunology, genomics/proteomics, neuro-science, and translational approaches in modeling IUI and fetal inflammation in an animal model that closely mimics the human pathology.