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

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.

Inappropriate accumulation of leukocytes is a shared feature in chronic inflammatory diseases such as rheumatoid arthritis (RA) and psoriatic arthritis (PsA), making this an attractive target for therapeutic intervention. We have identified a novel regulatory pathway, in which a B-cell derived peptide (PEPITEM) limits T-cell trafficking into inflamed tissues. This pathway is impaired in patients with RA, but can be rescued ex vivo with synthetic PEPITEM. We have preliminary data showing that PEPITEM therapy reduces disease severity in murine models of inflammatory arthritis.

To date no one has systemically dissected the molecular and cellular responses elicited by the adiponectin-PEPITEM pathway in chronic inflammation, or determined whether functional impairment of the pathway is a shared mechanism driving pathogenesis across chronic inflammatory diseases.

In this project, we want to understand the importance of the adiponectin-PEPITEM pathway in the development of RA and PsA, and to dissect the molecular mechanisms underpinning the functionality of the pathway and the use of PEPITEM as a new drug.

We will interrogate the functionality of the adiponectin-PEPITEM pathway in patients with RA and PsA to determine when functional impairment of the pathway occurs and whether it is a shared feature of disease pathology. Using murine models of arthritis, we will dissect the cellular and molecular responses to the pathway; how these are altered by functional loss of the pathway; and determine the therapeutic benefit of restoring the pathway in vivo.

Understanding the molecular mechanism underpinning the functionality of the adiponectin-PEPITEM pathway will provide important clues in pathology in RA and PsA, and more broadly other chronic inflammatory diseases. Current therapeutic strategies target pathogenic processes, but do not cure disease. Our approach is novel as it aims to restore a regulatory pathway to help switch off inflammation to cure disease.

We will improve our understanding of the cellular and molecular mechanism creating the protective effects of the adiponectin-PEPITEM pathway using RA and PsA as exemplar immune-mediated inflammatory diseases (IMIDs). We will thus impact on strategic goals of MRC in experimental medicine to "identify mechanisms of pathophysiology or disease, or to demonstrate proof-of-concept evidence of the validity and importance of new discoveries". We expect therefore that our research will have impact on basic research scientists, clinical scientists and clinicians, pharmaceutical industry and research charities.

1. Academic Beneficiaries
(a) Scientists. Innovations in analysing leukocyte trafficking and S1P biology in arthritis validated herein will have impact on the ongoing projects at the University of Birmingham and further afield. This project aims to improve our understanding the processes driving pathology in RA and PsA, specifically linked to the loss of an endogenous regulatory pathway, an area of intense research interest worldwide.

(b) Clinicians will benefit from the advancements in our understanding of cellular and molecular processes driving aberrant leukocyte accumulation and activation in RA and PsA, and how these are modified through different phases of disease gained from completing this project. Future clinical approaches may use biomarkers of the adiponectin-PEPITEM pathway to determine a patient's potential response to a pathway specific therapy; or use novel therapeutic strategies to restore endogenous regulatory pathways. Such biomarkers and therapies represent an innovative approach to the clinical management of RA and PsA, and more broadly in other IMIDs.

2. Training - Dedicated technical workshops and demonstration videos will be prepared as training tools for academics in a variety of cross-disciplinary fields. Additionally, this project will provide training and educational opportunities to the next generation of young scientists across disciplines. More specifically, postgraduates and postdocs who have trained in our laboratories have gone on the spread expertise in vitro and in vivo modelling of the type proposed here, and have been gainfully employed by other research groups and pharmaceutical industry. Our laboratories also frequently act as hosts to workers from laboratories around UK, providing training in specialised techniques.

3. Translational Research - We have a number of ongoing collaborations with clinical academics interested in "process driven pathology" in IMID and healthy aging. If we can reveal critical pathways that are shared across IMIDs, and/or show that restoring endogenous regulatory pathways is beneficial to the clinical management of IMIDs, this would have great impact on clinical research and pharmaceutical companies, and provide opportunities for interaction with industrial partners.

4. Economic and societal - In the long-term we hope for health benefits to patients suffering with RA and PsA, and more broadly other IMIDs, and economic benefits via industrial investment and discovery. These latter goals are likely to take of the order of ten years or more, but more intermediate success in identifying processes, pathways and targets linked to the functionality of the adiponectin-PEPITEM pathway and the potential to use this information to develop new drugs designed to restore endogenous regulatory pathways could follow in a few years after the end of this project.

5. Public - We also have a strong history of interaction with research charities as well as industry partners. Our work has and will be featured in their publicity and outreach activities, and we envisage the translational science proposed here leading to new concepts relevant to their goals, and opportunities for further research and fund-raising. We will take advantage of several events organised by the 3 Universities Public Engagement Working Groups to facilitate the public's awareness.