Anti-inflammatory drug target to reduce adverse pregnancy outcomes.

摘要 宫内感染/炎症(IUI)是早产和胎儿炎症的主要诱因，导致 胎儿器官如脑、肺和胃肠道的损伤反应。然而，这些机制和 由于缺乏相关的动物模型，精确的治疗方法仍然难以捉摸。我们有 开发了一种强有力的早产恒河猴宫内感染新模型：羊膜内感染(IA) 24小时后注射活的大肠杆菌，然后注射抗生素。此模型会产生持久的iUI。重要的是， 尽管大肠杆菌菌血症被清除，母婴炎症仍持续存在，导致早产。 (PTL)、胎儿免疫异常和胎儿神经炎。我们现在建议将IL1确认为药物靶点 用于IUI引起的早产和胎儿炎症。这项资助是基于我们的数据，Anakinra(IL1受体 临床用于类风湿性关节炎的拮抗剂)显著减少中性粒细胞在 母胎界面和羊水IL6、PGE2在不同但广泛使用的IA内毒素模型中。 此外，Anakinra还能逆转脂多糖诱导的胎儿脾中的“炎性Treg”。我们打算测试一下 在感染模型中，阿纳金纳将减少母婴残留炎症的假设 近距离模拟孕妇的IUI有两个目的。在目标1中，我们将询问抗IL1是否定向抗-IL1 炎症治疗可减少宫内感染引起的炎症和早产。我们将使用 最新的单细胞转录方法解开细胞和分子机制的研究 母胎交界处的炎症，定义了对IL1有反应的IUI的分娩相关途径 抑制力。利用多参数流式细胞术，我们将确定中性粒细胞募集和 绒毛膜-蜕膜的激活。在目标2中，我们将识别粘膜和系统性胎儿免疫紊乱 由一过性菌血症和无菌胎儿炎症引起。我们将确定Anakinra是否可以减少 IUI引起的胎儿全身炎症和神经性炎症。这些研究将发展关键的 为将来的研究提供知识库，旨在将Anakinra作为一种新的抗炎疗法 人性化人机界面。一个协作的多学科团队将使用高分辨率免疫学、基因组学/蛋白质组学、 神经科学和翻译方法在模拟IUI和胎儿炎症的动物模型中的应用 与人类的病理非常相似。

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.