Therapeutic targeting of fibroblast subsets in inflammatory arthritis

炎症性关节炎成纤维细胞亚群的治疗靶向

• 批准号: MR/S025308/1
• 负责人: Christopher Buckley
• 金额: $ 259.29万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS025308%2F1
• 关键词: Therapeutic; targeting; fibroblast; subsets; inflammatory

Inflammation is a healthy response to tissue damage, which helps to eliminate harmful microbes and repair organs. The factors that cause inflammation and subsequent tissue damage are usually very tightly regulated and opposed by factors that promote resolution and repair. A healthy inflammatory response has a rapid onset and an orderly resolution phase, in which activated immune cells initially recruited from the blood (called leucocytes) , exit the inflamed tissue and the resident tissue cells (called fibroblasts) return to their resting state. However it is not known how the various components of the "ecosystem" in disease are linked together to allow normal function of the affected tissue to be restored with minimal damage. Treatments aimed at leucocytes, traditionally thought to be the villains in arthritis, have proven to be limited in their ability to permanently switch off inflammation and prevent tissue damage. Our work uses new approaches to look directly at what happens to fibroblasts in the joint as arthritis progresses. Fibroblasts are often portrayed as the joint's housekeepers, performing maintenance jobs to keep the joint in good order. However in rheumatoid arthritis, a subset of fibroblasts becomes fundamentally altered. They overgrow, leading to the production of excess fluid and swelling within the joint. Furthermore these fibroblasts turn against the joint and begin to break down cartilage and bone. However there is a problem when it comes to targeting these cells as they come in different varieties, or subsets, only some of which become altered in disease. Our aim is to identify which subsets are most important in the development of arthritis and to explore whether changing them improves disease. Since different fibroblasts perform different functions in the joint, a key objective will be to determine which fibroblasts to target and which to ignore.Very little is known about how fibroblast subsets change during the course of human arthritis. Difficulties in sampling the joints involved and the lack of good fibroblast markers have all proved obstacles to such work. In the last few years we have addressed these limitations head on in the Birmingham Early Arthritis Clinic. Excitingly, in a new collaboration between colleagues in Oxford, Birmingham and Boston (USA) we have found that our new fibroblast markers can discriminate between fibroblasts that will mediate inflammation and cartilage and bone damage. We now plan to use the same markers to explore the fate and function of fibroblasts in an attempt to alter their behaviour. Targeting fibroblasts in this way will lead to a completely new approach to treating inflammatory arthritis; an approach that we are in a unique position to lead. Patients with rheumatoid arthritis in whom clinical remission has been achieved, subsequently relapse once drugs are withdrawn. This suggests that the factors responsible for complete resolution of inflammation remain to be discovered. This is why we are interested in fibroblasts. Our plan is to change the fibroblasts so that the joint can repair. However before we can attempt to do this in humans we have to be sure that we know how many subsets of fibroblasts exist in the joint, what their relationship is to one another and which variety of fibroblasts are responsible for inflammation and which is responsible for tissue damage. Furthermore we need to determine at what point during the course of the disease it is best to change the soil. Altering fibroblasts at the wrong time may make arthritis worse. Altering fibroblasts at the right time might cure the disease

炎症是对组织损伤的健康反应，有助于消除有害微生物和修复器官。导致炎症和随后的组织损伤的因素通常受到促进解决和修复的因素的严格调节和反对。健康的炎症反应具有快速发作和有序的消退阶段，其中最初从血液中招募的激活的免疫细胞（称为白细胞）退出发炎组织，并且驻留的组织细胞（称为成纤维细胞）返回到其静息状态。然而，目前尚不清楚疾病中“生态系统”的各种组成部分是如何联系在一起的，以使受影响组织的正常功能以最小的损伤恢复。针对白细胞的治疗，传统上被认为是关节炎中的恶棍，已被证明在永久关闭炎症和防止组织损伤的能力方面受到限制。我们的工作使用新的方法来直接观察关节炎进展时关节中的成纤维细胞发生了什么。成纤维细胞通常被描绘成关节的管家，执行维护工作，以保持关节良好的秩序。然而，在类风湿性关节炎中，成纤维细胞的一个子集发生了根本性的改变。它们过度生长，导致关节内产生多余的液体和肿胀。此外，这些成纤维细胞转而对抗关节并开始分解软骨和骨。然而，当涉及到靶向这些细胞时，存在一个问题，因为它们有不同的种类或子集，只有其中一些在疾病中发生改变。我们的目的是确定哪些亚群在关节炎的发展中最重要，并探索改变它们是否会改善疾病。由于不同的成纤维细胞在关节中执行不同的功能，因此一个关键的目标是确定哪些成纤维细胞可以靶向，哪些可以忽略。对相关关节取样的困难和缺乏良好的成纤维细胞标记都证明了这一工作的障碍。在过去的几年里，我们已经解决了这些限制在伯明翰早期关节炎诊所头上。令人兴奋的是，在牛津大学，伯明翰和波士顿（美国）的同事之间的一项新合作中，我们发现我们的新成纤维细胞标记物可以区分介导炎症和软骨和骨损伤的成纤维细胞。我们现在计划使用相同的标记来探索成纤维细胞的命运和功能，试图改变它们的行为。以这种方式靶向成纤维细胞将导致一种全新的治疗炎症性关节炎的方法;我们处于独特的位置来领导这种方法。类风湿性关节炎患者已达到临床缓解，随后一旦停药复发。这表明，负责完全解决炎症的因素仍有待发现。这就是为什么我们对成纤维细胞感兴趣。我们的计划是改变成纤维细胞，使关节可以修复。然而，在我们尝试在人类中这样做之前，我们必须确保我们知道有多少成纤维细胞亚群存在于关节中，它们之间的关系是什么，以及哪种成纤维细胞负责炎症，哪种负责组织损伤。此外，我们需要确定在疾病过程中的什么时候最好改变土壤。在错误的时间改变成纤维细胞可能会使关节炎恶化。在适当的时候改变成纤维细胞可能会治愈这种疾病

项目成果

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

• DOI: 10.1016/j.cell.2022.01.012
• 发表时间: 2022-03-03
• 期刊: Cell
• 影响因子: 64.5
• 作者: COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium. Electronic address: [e-mail];COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium
• 通讯作者: COvid-19 Multi-omics Blood ATlas (COMBAT) Consortium

Distinct fibroblast subsets drive inflammation and damage in arthritis

• DOI: 10.1038/s41586-019-1263-7
• 发表时间: 2019-06-13
• 期刊: NATURE
• 影响因子: 64.8
• 作者: Croft, Adam P.;Campos, Joana;Buckley, Christopher D.
• 通讯作者: Buckley, Christopher D.