New therapeutic avenues in inflammatory arthritis: exploring the role of the adiponectin-PEPITEM pathway

背景：在健康情况下，免疫细胞离开血液进入炎症组织以帮助组织修复。它们在血管中的移动受到一系列“安全检查站”的控制。然而，组织中免疫细胞的不适当积累是慢性炎症性疾病的共同特征，包括类风湿关节炎（RA）和银屑病关节炎（PsA）。我们最近发现了一个新的检查点（脂联素- pepitem途径），它通常会阻止免疫细胞进入组织。在类风湿性关节炎（RA）和其他慢性炎症性疾病中，这个检查点丢失，使破坏性免疫细胞不适当地进入关节。至关重要的是，我们可以通过在实验室中用PEPITEM治疗患者的免疫细胞来逆转这种缺陷。我们现在有一些初步的证据表明，当我们用PEPITEM治疗小鼠时，我们可以限制关节炎的严重程度和进入关节的免疫细胞的数量。目的：在本项目中，我们想了解脂联素- pepitem通路在RA和PsA发展中的重要性。特别是，我们将发现响应该途径而发生的精确的细胞和分子变化；在疾病病理和通路缺失的情况下，这些是如何改变的；以及使用PEPITEM作为新药的潜在好处是什么。方法：为了实现这一目标，我们将在三所大学（伯明翰、格拉斯哥和纽卡斯尔）建立一个跨越多学科（生物学、风湿病学、分析化学、免疫学、医学和生物统计学）的新研究团队。我们将结合研究不同炎症性关节炎（RA vs PsA）、RA不同阶段（早期vs晚期）患者的临床样本，以及关节炎的动物模型。我们将确定脂联素- pepitem通路的缺失是否发生在所有炎症性关节炎患者中，还是仅仅发生在一个亚群中。这将为我们提供一种新的工具来识别对基于pepitem的治疗有反应的患者。使用关节炎小鼠模型，我们将解剖控制脂联素- pepitem途径生物活性的细胞和分子机制，以真正了解它如何控制组织损伤。最后，我们将确定用PEPITEM治疗关节炎小鼠是否可以预防持续性疾病，因为我们相信恢复正常的PEPITEM功能有可能通过恢复安全检查点来关闭炎症。利用：我们认为了解PEPITEM的生物学将为RA和PsA的发展，以及更广泛的其他免疫介导的炎症性疾病（IMIDs）提供重要线索。目前的治疗策略针对致病过程，但不能治愈关节炎。我们的方法是新颖的，因为它旨在了解恢复自然发生的抑制性脂联素- pepitem途径是否有助于关闭关节炎并治愈疾病。患者受益：我们研究的目的是改善被诊断患有关节炎（和其他IMIDs）的患者的预后，并最终帮助治愈疾病。我们的研究将通过观察RA和PsA中脂联素- pepitem通路的异同，以及早期疾病与晚期疾病的异同，帮助对患者进行分层。这为开发针对脂联素- pepitem通路的药物提供了一个革命性的机会，这样在该通路上有缺陷的患者就可以获得对他们有效的治疗，并有可能治愈他们的疾病。这将使患者能够更好地进行临床管理，提高生活质量，这肯定会对患有慢性炎症疾病的人产生积极影响。

BACKGROUND: In health, immune cells leave the blood and enter inflamed tissue in order to help tissue repair. Their movement across blood vessels is controlled by a series of 'security check-points'. However, inappropriate accumulation of immune cells in tissue is a common feature of chronic inflammatory diseases, including rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We have recently identified a new check-point (adiponectin-PEPITEM pathway) that normally blocks the entry of immune cells into tissues. In rheumatoid arthritis (RA) and other chronic inflammatory diseases, this check-point is lost, allowing inappropriate access of destructive immune cells into the joint. Crucially, we can reverse this defect by treating patient immune cells with PEPITEM in the laboratory. We now have some preliminary evidence that suggests we can limit the severity of arthritis and the number of immune cells entering into the joint when we treat mice with PEPITEM. PURPOSE: In this project, we want to understand the importance of the adiponectin-PEPITEM pathway in the development of RA and PsA. In particular we will discover the precise cellular and molecular changes that occur in response to the pathway; how these are altered in disease pathology and in the absence of the pathway; and what are the potential benefits of using PEPITEM as a new drug. METHODOLOGY: In order to achieve this, we will build a new research team spanning multiple disciplines (biology, rheumatology, analytical chemistry, immunology, medicine and biostatistics) across three Universities (Birmingham, Glasgow and Newcastle). We will use a combination of studies on clinical samples from patients with different inflammatory arthritides (RA vs PsA) and at different stages of RA (early vs late), and animal models of arthritis. We will determine whether loss of the adiponectin-PEPITEM pathway occurs in all patients with inflammatory arthritides or just a subpopulation. This will provide us with a novel tool to identify patients that would respond to a PEPITEM-based therapy. Using arthritic mice models, we will then dissect the cellular and molecular mechanism governing the bioactivity of the adiponectin-PEPITEM pathway to truly understand how it controls tissue damage. Finally we will establish whether treating arthritic mice with PEPITEM can prevent persistent disease, as we believe that restoring normal PEPITEM function has the potential to switch off inflammation by reinstating the security check-point. EXPLOITATION: We think that understanding the biology of PEPITEM will provide important clues in the development of RA and PsA, and more broadly other immune-mediated inflammatory diseases (IMIDs). Current therapeutic strategies target pathogenic processes, but do not cure arthritis. Our approach is novel as it aims to learn if restoring the naturally occurring inhibitory adiponectin-PEPITEM pathway can help switch off arthritis and cure the disease. PATIENT BENEFIT: The aim of our research is to improve the outcome for patients diagnosed with arthritis (and other IMIDs) and ultimately help to cure the disease. Our research will help stratify patients by looking at the similarities and differences in the adiponectin-PEPITEM pathway in RA and PsA, and also in early disease compared to late disease. This presents a revolutionary opportunity to develop drugs that target the adiponectin-PEPITEM pathway so that patients who have a defect in this pathway can access treatment that is effective for them and can potentially cure their disease. This will enable better clinical management of patients and better quality of life, which certainly will have a positive impact on people living with chronic inflammatory diseases.