Therapeutic targeting of fibroblast subsets in inflammatory arthritis

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

In this programme we will use functional single cell based approaches combined with fate mapping techniques in mice to test the hypothesis that distinct synovial fibroblast subsets, residing either in the lining or sub-lining layer, differentially mediate synovial inflammation and tissue damage; which we propose can then be selectively therapeutically targeted. To do this we will initially explore how the fibroblast subsets that we have identified change during the development of arthritis and during the switch from resolving to persistent disease in order to determine the functional consequences of these changes in relation to inflammation, damage and repair. Next we will determine the developmental origins and interrelationships between synovial fibroblast subsets in the lining and sub-lining layers of the synovium and observe how selective deletion of these subsets or changes in their biology alter the balance between persistent inflammation and tissue damage during the development of arthritis. Finally we will determine the relationship between alterations in fibroblast subsets and disease outcome during the development of human rheumatoid arthritis. A key strength of our work is that it combines both human and animal studies that run in parallel. An advantage of this approach is that we will minimize over reliance on mouse models of disease. This will place us in an ideal position to translate our findings into benefits for patients with inflammatory arthritis in general and rheumatoid arthritis in particular. Our studies represent an important step forward in the treatment of Immune Mediated Inflammatory Diseases as they allow the identification and therapeutic manipulation of discrete subsets of fibroblasts with the hope of modulating inflammation and cartilage/bone damage in the absence of immune suppression

This ambitious and transformative programme of work aims to investigate the therapeutic potential of targeting pathogenic fibroblast subsets in chronic inflammatory arthritis. Our ultimate goal is to identify novel therapeutic targets and, in the long term, to deliver effective treatment pathways that will improve patient quality of life and reduce the economic burden on the UK healthcare system.
The multidisciplinary nature of this project will ensure significant impact on a range of scientific and clinical fields that are underpinned by inflammation and immune cell biology. For basic and clinician scientists, our work will enhance the depth of understanding of chronic inflammatory disease pathogenesis as well as further the knowledge in immune and inflammatory signalling pathways, cancer biology and animal experimentation.
Our unique set up is cross-institutional and cross site. Through co-location with NIHR Clinical Research Facility's inflammation arm, the Inflammation Research Facility (IRF), is well placed to personalise our research to the clinical objective and nurture patient-researcher relationships. The Rheumatology Research Group (RRG) enables patients in the region to have their say on the research that we do. Our engagement with R2P2 will foster the patient-focussed element of the research and ensure we understand what relevance our research can have to benefit patients.
Engagement with patients and the general public is critical to our success, and we have plans to exploit several opportunities through seminars, workshops and training events. Additionally, this project will provide training and educational opportunities to the next generation of young scientists across a range of disciplines. The two appointed post-doctoral research fellows on this project will benefit from working within a multi-disciplinary team, and have strong opportunities for development of transferrable research skills. They will also be encouraged to engage with patient partners in order to strengthen their non-scientific communication skills.