Investigating the lymphatic system in intestinal inflammation

背景和临床相关性炎症性肠病（IBD），包括克罗恩病（CD）和溃疡性结肠炎（UC），是一种主要影响胃肠道的慢性免疫介导的炎症性疾病。欧洲有200多万人受到影响，患病率超过0.3%，发展中国家的发病率正在上升。多种遗传和环境因素与IBD的发展有关，但仍未完全了解。目前已有几种治疗IBD的药物；然而，这些疗法都不能导致永久的无药物缓解状态，因此最佳管理仍然是一个主要的临床挑战。对治疗的不同反应表明，随着时间的推移，潜在的疾病过程不同，并强调需要更深入地了解IBD的细胞基础，以开发创新的治疗方法。淋巴系统是与血管平行的血管系统，广泛分布于全身。它们在允许多余的液体回流到心脏方面起着关键作用，因此有助于维持体内的液体平衡。此外，它们在促进适当的免疫反应方面发挥着重要作用。它们在炎症中的作用相对被忽视，尽管有几篇报道称克罗恩病和溃疡性结肠炎患者的活组织检查发现肠道中淋巴管密度增加。最近出现的证据表明，在IBD中，免疫细胞和液体通过淋巴管流出的区域似乎在从肠道流出的区域受损，证实IBD与淋巴管可观察到的结构变化有关。尽管有这些描述性的报道，但尚不清楚淋巴功能改变对IBD炎症消退的影响程度。动物模型实验为淋巴在炎症中的作用提供了有价值的见解。我们知道，在小鼠模型中，刺激淋巴管生长（淋巴管生成）可以改善结肠、皮肤、关节和心脏的炎症。此外，在小鼠模型中，淋巴系统的抑制加重了结肠炎症、皮肤炎症、关节炎和心脏病发作的消退。这突出了免疫细胞淋巴引流的重要性，以使炎症得以解决。这些报告强烈提示淋巴系统可能是改善炎症的一种途径，因此值得进一步研究IBD。实验目的和目的，以及潜在的应用和益处关于结肠淋巴对炎症反应和消退的改变知之甚少。新技术正在出现，可以在结肠中对单个细胞进行研究和表征。我们将使用这些来研究淋巴内皮细胞的变异以及淋巴细胞和它们在结肠中的调节因子之间的相互作用。这将使我们对这些船只的作用有一个急需的了解。一旦项目的这一部分完成，我们将继续使用结肠炎动物模型测试如何操纵淋巴系统影响结肠炎症的解决。了解肠道炎症消退的机制将有助于最终实现将其转化为治疗性的，以关闭肠道中的慢性炎症，并有助于治疗IBD患者。

Context and clinical relevanceInflammatory bowel disease (IBD), comprising of Crohn's Disease (CD) and Ulcerative Colitis (UC), is a chronic immune-mediated inflammatory disease that predominantly affects the gastrointestinal tract. Over two million people in Europe are affected with a prevalence exceeding 0.3% and its incidence is rising in the developing world. Various genetic and environmental factors have been implicated in the development of IBD but it remains incompletely understood. Several drug classes exist to treat IBD; however, none of these therapies lead to a state of permanent drug free remission and so optimal management remains a major clinical challenge. The variable response to treatment suggests different underlying disease processes over time and highlights the need for a deeper understanding of the cellular basis of IBD in order to develop innovative therapeutics.Lymphatics as a mechanism to allow exit of inflammatory cellsLymphatic vessels are a parallel vascular system to the blood vessels and are widely distributed across the body. They have a key role in permitting excess fluid to drain back to the heart and so serve to maintain fluid balance in the body. Furthermore, they play an essential role in facilitating an appropriate immune response. Their role in inflammation has been relatively neglected despite several reports of biopsies from patients with both Crohn's Disease and Ulcerative Colitis identifying increased lymphatic vessel density in the intestine. More recently evidence has emerged that in IBD the outflow of immune cells and fluid through the lymphatic vessels appears to be impaired in areas draining from the gut confirming that IBD is associated with observable structural changes in the lymphatic vessels. Despite these descriptive reports, it is unclear to what degree altered lymphatic function impacts on the resolution of inflammation in IBD.Experiments with animal models have provided valuable insights into the role of the lymphatics in inflammation. We know that the stimulation of lymphatic vessel growth (lymphangiogenesis) in mouse models improves inflammation in the colon, as well as the skin, joint and heart. Furthermore, inhibition of lymphatics worsens colonic inflammation, skin inflammation, arthritis and resolution from heart attack in mouse models. This highlights the importance of adequate lymphatic drainage of immune cells to allow resolution of inflammation. These reports strongly suggest that the lymphatic system is a possible way to improve inflammation and thus warrants further study in IBD.Experimental aims and objectives, and potential applications and benefitsLittle is known regarding the alterations in colonic lymphatics in response to inflammation and resolution. New technologies are emerging which allow individual cells to be investigated and characterised in the colon. We will use these to study variation in lymphatic endothelial cells as well as the interactions between lymphatic cells and their regulators in the colon. This will enable us to develop a much-needed understanding of what these vessels are doing. Once this part of the project is achieved we will proceed to test how manipulating the lymphatic system affects the resolution of colonic inflammation using animal models of colitis. Understanding the mechanisms of the resolution of intestinal inflammation will help serve the ultimate aim of translating this therapeutically to switch off chronic inflammation in the gut and help to treat patients with IBD.