Award Title: Targeting pathogenic fibroblasts in immune mediated inflammatory disease
Funder: Versus Arthritis

Abstract: Rheumatoid arthritis (RA) and Sjögren's Syndrome (SjS) are both autoimmune mediated inflammatory diseases characterised by persistent tissue inflammation and damage[1,2]. While in RA, inflammation localises to synovial joints leading to arthritis, cartilage and bone damage, SjS is a disabling systemic disease characterised by pain, fatigue and mucosal dryness, with risk of systemic complications (joints, lungs, skin, and peripheral nerves being the most frequently involved) in 30–50% of patients. In SjS, there is no effective immunomodulatory treatment for disease-related systemic complications. Whilst in RA, the introduction of biological drugs targeting either leucocytes or their derived products has led to a step change in management, however 30-40% of patients do not respond to treatment, regardless of the mechanism of action of the drug used and up to 15% of individuals develop multi-drug resistance (treatment refractory disease). Collectively, these observations suggest the existence of additional pathways of disease persistence that remain to be targeted therapeutically.
Fibroblasts are heterogeneous and have diverse effector roles in disease pathology including different immunological properties depending on their tissue of origin. We have recently identified a pathogenic subset of fibroblasts present in the joints of patients with active RA despite treatment and in patients with active SjS. In RA, these immune-modulatory fibroblasts express high levels of the cell-surface glycoprotein fibroblast activation protein-α (FAPα) and contribute to disease pathology by “usurping” the joint microenvironment, producing pathogenic levels of chemokines and cytokines that modify the quality, quantity and duration of leucocyte accumulation. In SjS, the same biomarker (FAPa) identifies a population of immune effector fibroblasts that supports the development and maintenance of ectopic tertiary lymphoid structures, a key pathological feature of the disease. Experimental deletion of FAPa expressing fibroblasts in transgenic mouse models of joint and salivary gland inflammation resulted in attenuated tissue inflammation and damage.
These data provide a clear rationale for the therapeutic targeting of FAPα expressing fibroblasts in both RA and SjS using a targeted cell depletion strategy. 
Recent breakthroughs in cancer therapy have been achieved by redirecting cytotoxic T cells to recognise specific antigens on cancer cells using a chimeric antigen receptor (CAR). The modified T cells effectively eliminate cancer cells, and CAR-T cell therapy has been approved for the treatment of some forms of haematological malignancy and are under investigation for use in autoimmune diseases, such as Lupus.
Our project collaborators (JE) have shown that the adoptive transfer of CAR-T cells directed against FAPα leads to a significant reduction in fibrosis and restoration of function after cardiac injury in mice, an effect mediated through the direct ablation of FAPα expressing cardiac fibroblasts.
In this project we aim to use FAPα-CAR-T cells to selectively deplete FAPα expressing synovial fibroblasts to attenuate synovial inflammation and damage in arthritis. If successful, this study will provide ‘proof-of-principle’ for the therapeutic efficacy of targeting synovial fibroblasts in RA, using specifically engineered CAR-T cells.


Research Activity Codes: 5.2 CELLULAR AND GENE THERAPIES
Health Categories: MUSCULOSKELETAL