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

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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.