Investigating the lymphatic system in intestinal inflammation

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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.