Pro-inflammatory lung dendritic cells in stratified severe RSV bronchiolitis

背景：呼吸道合胞病毒（RSV）是世界范围内引起婴幼儿肺部感染的最常见原因，称为毛细支气管炎，可导致严重疾病和偶尔死亡。没有疫苗接种或特殊治疗。由于治疗费用和更广泛社会的费用（例如父母/照顾者的工作损失天数），呼吸道合流病毒造成了重大的经济负担。在英国，有2%的婴儿因呼吸道合胞病毒细支气管炎而住院，其中一些人会发展成非常严重的疾病，有时甚至会危及生命，导致呼吸衰竭。这些婴儿需要呼吸支持，机器给他们的肺充气。这通常只需要几天，但在这些非常严重的病例中，有三分之一的疾病没有迅速改善，因此需要更长时间的机器呼吸支持。呼吸道合胞病毒细支气管炎的呼吸问题被认为是由于肺部呼吸管小端非常严重的炎症。维持这种炎症和延缓疾病改善的机制尚不清楚。小鼠模型的研究表明，两种类型的免疫细胞在RSV感染后的肺部炎症中起重要作用；其中一种叫做T细胞，另一种叫做树突状细胞（dc），它们是T细胞的主要激活剂。试点数据：在一项针对呼吸道合胞病毒毛细支气管炎患儿的试点研究中，我们最近在小肺洗液中检测到大量的dc和T细胞。健康未感染肺的婴儿洗肺不含这些细胞。假设和项目计划：我们假设激活的肺dc和T细胞可导致炎症，是持续炎症和延迟持续较长时间的严重RSV细支气管炎婴儿疾病改善的原因。我们将对患有严重呼吸道合胞病毒疾病的使用机器呼吸支持的婴儿进行小肺冲洗，比较那些只需要短暂呼吸支持的婴儿和那些需要较长时间呼吸支持的婴儿。在肺洗液中，我们将计数dc和不同组的T细胞，测量dc的激活和它们激活T细胞的能力，我们将发现洗液中的信号物质是否能够导致dc的发展和/或激活。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从小鼠中取出，然后替换它们。展望：如果我们发现激活的肺dc和相关T细胞在严重的持久RSV细支气管炎中负责维持炎症和延迟疾病的改善，这些研究将确定肺dc作为开发新的抗炎疗法的有希望的靶点。此外，肺DC的数量和性质也可作为预测严重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.