Pro-inflammatory lung dendritic cells in stratified severe RSV bronchiolitis

背景技术背景：呼吸道合胞病毒（RSV）是世界范围内婴儿和幼儿胸部感染的最常见原因，称为细支气管炎，可导致严重疾病，偶尔死亡。没有接种疫苗或特殊治疗。由于治疗成本和更广泛的社会成本（例如父母/护理人员的工作日损失），RSV造成了重大的经济负担。在英国，2%的婴儿必须因RSV细支气管炎住院，其中一些婴儿发展为非常严重的，有时危及生命的疾病，导致呼吸衰竭。这些婴儿需要呼吸支持，机器会给他们的肺充气。这通常只需要几天，但在这些非常严重的病例中，有三分之一的疾病无法迅速改善，需要更长的机器呼吸支持。RSV细支气管炎的呼吸问题被认为是由于肺部呼吸管小端的非常严重的炎症。维持这种炎症和延迟疾病改善的机制尚不清楚。在小鼠模型中的工作表明，两种类型的免疫细胞在RSV感染后的肺部炎症中具有重要作用;其中一种称为T细胞，另一种称为树突状细胞（DC），它们是T细胞的主要激活剂。试点数据：在一项对呼吸机辅助呼吸的RSV细支气管炎婴儿的初步研究中，我们最近在小的肺洗液中检测到大量的DC和T细胞。健康未感染肺的婴儿的肺洗液不含这些细胞。 假设和项目计划：我们假设，活化的肺DC和T细胞可导致炎症，是持续炎症和延迟改善的婴儿与持续较长时间的严重RSV细支气管炎的疾病的原因。我们将从患有严重RSV疾病的婴儿中进行少量的肺冲洗，这些婴儿正在接受机器呼吸支持，将那些只需要短暂支持的婴儿与那些需要更长时间支持的婴儿进行比较。在肺洗液中，我们将计数DC和不同组的T细胞，测量DC的活化及其活化T细胞的能力，并且我们将发现洗液中的信号物质是否能够引起DC的发育和/或活化。然后，我们将使用RSV感染的小鼠模型来证明或反驳DC是维持炎症所必需的，方法是将DC从小鼠体内取出，然后替换它们。展望：如果我们发现活化的肺DC和相关的T细胞负责维持炎症和延迟严重持久RSV细支气管炎中疾病的改善，这些研究将确定肺DC作为开发这种疾病的新抗炎疗法的有希望的靶点。此外，肺DC的数量和性质也可用作预测严重RSV疾病延迟消退的标志物。

BACKGROUND: Respiratory syncytial virus (RSV) is worldwide the most common cause of a type of chest infections in babies and toddlers called bronchiolitis, which can cause severe disease and occasionally death. Vaccination or specific treatment is not available. Due to treatment costs and costs for the wider society (e.g. days lost at work for parents/ carers) RSV is responsible for a major financial burden. 2% of all babies in the UK have to be admitted to hospital with RSV bronchiolitis and some of them develop very severe and sometimes life threatening disease which causes breathing to fail. These babies require breathing support where a machine inflates their lungs. This is usually only required for a few days, but in a third of these very severe cases the disease fails to improve quickly making longer machine breathing support necessary. Breathing problems in RSV bronchiolitis are thought to be due to very severe inflammation of the small ends of the breathing tubes in the lung. The mechanisms that maintain this inflammation and delay improvement of disease are not well understood. Work in mouse models suggests that two types if immune cells have important roles in lung inflammation after RSV infection; one of these are called T cells and the other dendritic cells (DCs) which are the main activators of T cells. PILOT DATA: In a pilot study of infants with RSV bronchiolitis who were on machine breathing support, we have recently detected substantial numbers of DCs and T cells in small lung washes. Lung washes of infants with healthy uninfected lungs do not contain these cells. HYPOTHESIS AND PROJECT PLaN: We hypothesise that activated lung DCs and T cells which can lead to inflammation, are responsible for continuing inflammation and the delay in improvement of disease in babies with longer lasting severe RSV bronchiolitis. We will take small lung washes from babies with severe RSV disease who are on machine breathing support comparing those who only need this support briefly to those who require it for a longer time. In the lung washes we will count DCs and different groups of T cells, measure the activation of DCs and their ability to activate T cells and we will find out if signal substances in the wash fluid are able to cause the development and / or activation of DCs. We will then use the mouse model of RSV infection to prove or disprove that DCs are required to maintain inflammation by taking DCs out of the mouse and then replacing them. OUTLOOK: If we find that activated lung DCs and associated T cells are responsible for maintaining inflammation and delaying improvement of disease in severe long lasting RSV bronchiolitis, these studies will identify lung DCs as a promising target for the development of new anti-inflammatory therapies for this condition. In addition numbers and properties of lung DC may also be useful as a marker to predict delayed resoltion of severe RSV disease.