Determination of the trafficking kinetics and role of mononuclear phagocyte subsets in treatment-naive psoriatic arthritis.

确定单核吞噬细胞亚群在初治银屑病关节炎中的运输动力学和作用。

• 批准号: MR/V006592/1
• 负责人: Joseph Hutton
• 金额: $ 43.36万
• 依托单位: University of Cambridge
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FV006592%2F1
• 关键词: Determination; trafficking; kinetics; role; mononuclear

BackgroundPsoriatic arthritis is a condition caused by inflammation in the joints, leading them to become painful, stiff, and swollen. These symptoms are caused by immune system cells which travel into joints and cause damage. It can also cause other health problems, and a loss of about 3 years of life expectancy. The condition is expensive to treat, costing about £183 million per year to the NHS. The immune system is important in the development of psoriatic arthritis. Psoriatic arthritis is less studied than other conditions and this needs to be addressed.ContextThis research looks at a group of cells called "mononuclear phagocytes" which can attract and turn on other immune cells, causing a cycle of ongoing damage. Normally, immune cells move around the body in the blood, and only move into other places when they sense infection or damage. Healthy joints therefore contain few immune cells. In psoriatic arthritis, immune cells including mononuclear phagocytes move into the joints where they cause pain and damage. We do not understand what causes cells to move in this way. Identifying what causes the cells to move and controls their behaviour in the joint could provide a way of preventing immune cells from entering the joints, leading to new treatments. Recent advances in our understanding of mononuclear phagocytes have been made, including better ways to identify cells and discovery of new "inflammatory" cells important in other diseases. These findings have not been applied to arthritis. I aim to use the latest information and apply new techniques to better understand the behaviour of cells and track them in people with psoriatic arthritis. I will compare this against cells in the blood and joints of healthy people, and people with other forms of arthritis to see why psoriatic arthritis behaves differently.Research planI will identify and compare the immune cells in the blood and joints from clinical samples from arthritis clinics to those from people without arthritis, so our findings reflect real patients. I plan to investigate how the immune cells in the joints of people with arthritis are different from those without arthritis. I want to see which kinds of immune cells are in both the bloodstream and the joints, what the cells do in the joint, and what joint-damaging substances they release. This will tell us which immune cells are driving arthritis, how quickly they move from the blood into joints, and what makes the immune cells in psoriatic arthritis behave differently to those in healthy people. I will study the cells in the lab to determine how they interact with blood vessels to get into joints, and what joint-damaging substances they release when different triggers are applied. Finally, I will "tag" immune cells from participants so they can be seen using a special camera. These will then be reinjected into the bloodstream of the same person to watch how the cells move into the joints.Who and whereI will carry out this project at the University of Cambridge where we have developed the techniques to carry out these experiments. As well as being a researcher, I am a training rheumatologist, a doctor who specialises in joints and joint disease.ImportanceThis is a laboratory-based research study designed to understand how the cells that cause arthritis and its symptoms move into joints to trigger disease. This knowledge can then be used to design new treatments to stop or prevent immune cells from inappropriately entering joints. This may make treatments work better and reduce side-effects. The methods of "tagging" cells and seeing where they go in the body will also help to test if medications work for certain conditions. In addition, these findings may help understand other diseases where mononuclear phagocytes are important such as atherosclerosis and inflammatory bowel disease and develop new treatments for them.

背景银屑病关节炎是一种由关节炎症引起的疾病，导致关节疼痛、僵硬和肿胀。这些症状是由免疫系统细胞引起的，这些细胞进入关节并造成损害。它还可能导致其他健康问题，以及大约3年的预期寿命损失。这种情况的治疗费用很高，NHS每年花费约1.83亿英镑。免疫系统在银屑病关节炎的发展中很重要。银屑病关节炎比其他疾病研究得更少，这需要解决。上下文这项研究着眼于一组称为“单核吞噬细胞”的细胞，它们可以吸引并打开其他免疫细胞，造成一个持续的损伤循环。正常情况下，免疫细胞在血液中围绕身体移动，只有当它们感觉到感染或损伤时才会移动到其他地方。因此，健康的关节含有很少的免疫细胞。在银屑病关节炎中，包括单核吞噬细胞在内的免疫细胞移动到关节中，在那里它们引起疼痛和损伤。我们不知道是什么导致细胞以这种方式移动。确定是什么导致细胞移动并控制它们在关节中的行为，可以提供一种防止免疫细胞进入关节的方法，从而导致新的治疗方法。最近我们对单核吞噬细胞的理解取得了进展，包括更好的方法来识别细胞和发现在其他疾病中重要的新的“炎性”细胞。这些发现并不适用于关节炎。我的目标是使用最新的信息和应用新技术，以更好地了解细胞的行为，并在银屑病关节炎患者中跟踪它们。我将把它与健康人和其他关节炎患者的血液和关节中的细胞进行比较，看看为什么银屑病关节炎的表现不同。研究计划我将识别和比较血液和关节中的免疫细胞，这些免疫细胞来自关节炎诊所的临床样本，来自没有关节炎的人，所以我们的发现反映了真实的患者。我计划研究关节炎患者关节中的免疫细胞与非关节炎患者的免疫细胞有何不同。我想知道血液和关节中都有哪些免疫细胞，这些细胞在关节中起什么作用，以及它们释放出什么破坏关节的物质。这将告诉我们哪些免疫细胞在驱动关节炎，它们从血液进入关节的速度有多快，以及是什么使银屑病关节炎中的免疫细胞与健康人的免疫细胞表现不同。我将在实验室中研究这些细胞，以确定它们如何与血管相互作用进入关节，以及当应用不同的触发器时，它们释放出哪些破坏关节的物质。最后，我将“标记”参与者的免疫细胞，以便使用特殊的相机可以看到它们。然后这些细胞将被重新注入同一个人的血液中，观察细胞是如何移入关节的。Who and WhereI将在剑桥大学进行这个项目，在那里我们开发了进行这些实验的技术。除了作为一名研究人员，我还是一名培训风湿病学家，一名专门研究关节和关节疾病的医生。重要性这是一项基于实验室的研究，旨在了解导致关节炎及其症状的细胞如何进入关节引发疾病。然后，这些知识可以用于设计新的治疗方法，以阻止或防止免疫细胞不适当地进入关节。这可能会使治疗效果更好，并减少副作用。“标记”细胞并观察它们在体内的位置的方法也将有助于测试药物是否对某些情况有效。此外，这些发现可能有助于了解单核吞噬细胞重要的其他疾病，如动脉粥样硬化和炎症性肠病，并为它们开发新的治疗方法。