Pre-Clinical Proof of Concept Studies with Industry Partners

The Centre for Arthritis and Rheumatic diseases (SVUH, UCD) and Molecular Rheumatology (TCD) have developed a number of industry partnerships around drug discovery and translational research. These studies utilize the ex vivo whole tissue synovial explant model, sorted synovial cells and multiplex protein assays, transcriptomics and a systems biology approach to establish pre-clinical drug development studies of novel biotherapeutics and small molecular weight candidates.

Autoantibodies and Disease Pathogenesis

RA disability stems from structural damage of cartilage and bone due to erosions in synovial joints, if not treated early and aggressively. Treatment guidelines are based on clinical factors such as rheumatoid factor (RF), and more recently, presence of the autoantibodies anti-citrullinated peptide antibodies (ACPA), which may provide improved prediction of outcome in RA. The association with ACPA appears to be highly specific to RA, indeed these antibodies may be present before the onset of clinical arthritis, in some cases several years before, suggesting that autoimmunity precedes inflammation. Autoantibodies against citrullinated proteins are among the strongest risk factors for bone destruction. This implies a direct link between autoantibody response and structural bone damage in RA. In this study we propose to improve the early diagnosis and prognosis of RA patients by examining the role of ACPA positivity on immune cell function and synovial invasiveness. Specifically, we are stratifying pre-RA and RA patients using ACPA positivity, erosive status and immunopathology of synovial T and B cells in high-risk, poor outcome or good prognosis groups. Phenotype and functional characterisation of T cells and B cells isolated from the site of inflammation in ACPA+ vs ACPA- patients, and their reciprocal interactions and subsequent effect on synovial invasive mechanisms are being examined. Finally, a functional genomics and systems biology approach for disease onset, progression and response is being utilised. Combining clinical status, immunopathology, immune function and transcriptomics analysis from ACPA+ vs ACPA- patients will provide valuable insight into the diagnosis and prognosis of patients with RA at an earlier stage of disease than is currently possible and this will allow selection of treatment for specific patients based on a sound, scientific rationale.

Hypoxia, Metabolism and Inflammatory Arthritis

Mitochondrial respiration is the main source of metabolic energy in cells by generating adenosine-triphosphate (ATP) in an oxygen-dependent manner.  Environmental cues such as the availability of nutrients and oxygen are sensed by mTOR, AMPK and HIF-1α together with inflammatory cell activation signals to determine the outcome of cell activation and differentiation. We have previously demonstrated that efficiency of oxygen supply to the synovium is poor due to the highly dysregulated synovial microvasculature. This, along with the increased energy demands of activated infiltrating immune cells and inflamed resident cells, leads to an hypoxic microenvironment and mitochondrial dysfunction. This favours an increase in reactive oxygen species, leading to oxidative damage which further promotes inflammation. In this adverse microenvironment synovial cells adapt and rapidly produce ATP to maintain cell activation/function and switch their cell metabolism from a resting regulatory state to a highly metabolically active state. This allows them to produce essential building blocks to support their proliferation. Therefore, metabolic-reprogramming of synovial cells may provide novel therapeutic strategies for treatment of inflammatory arthritis.  However, the inflamed synovial tissue is composed of many different cell types including macrophages, T-and B-cells, dendritic cells, endothelial cells and synovial fibroblasts which through cell-cell interactions drive synovial invasiveness, thus making the understanding of these pathways very complex. Therefore, our research programme aims to define the metabolic profile and signalling pathways in specific cell types isolated from the joint and in ex vivo organotypic synovial explant tissue from patients with IA. We have demonstrated distinct metabolic profiles and transcriptional signatures in specific cell types isolated from the joint. Furthermore, we have identified distinct subsets within specific cell types that differ in their metabolic profile, an effect that impacts on whether the cell is pro-inflammatory or pro-resolution.  Finally, we have identified that these changes occur very early in disease and can even be present pre-disease onset. Our ongoing work examines the therapeutic potential of targeting metabolic pathways using in-vitro, ex-vivo and in-vivo models.