We have a longstanding interest in research on Rheumatoid Arthritis (RA) and related rheumatological diseases. Despite recent treatment advances, many patients do not respond to current therapies and sustained disease remission is still rare. To address this problem, our current projects focus on new immune and inflammatory pathways that drive arthritis. Ultimately, we hope to translate research into the clinic to benefit patients. Funding from Arthritis Australia has allowed us to investigate how joint inflammatory cells can be selectively targeted in a preclinical model of arthritis. Results from this study offer a new therapeutic option for consideration in RA but also other inflammatory joint diseases.
Abnormal cell survival can cause cancers but also contribute to chronic inflammation in diseases such as RA. WEHI has been at the forefront of research to understand the molecular pathways governing cell survival and cell death. A suite of molecular targets have been identified and antagonists have been developed. Recently, this research led to the introduction of Venetoclax as a new treatment for leukaemia. The grant set out to identify how inflammatory cells persist in arthritic joints and whether existing drugs that target pro-survival proteins can be similarly used to alleviate joint inflammation while maintaining cells in other organs. This is important because current drugs for RA can deplete immune cells outside the inflamed joints, leading to compromised immunity in patients.
Chronic inflammation in RA is characterised by the recruitment of inflammatory immune cells from the blood into arthritic joints. One of these cells are called neutrophils. They are known to drive joint inflammation by producing noxious factors. Once neutrophils enter affected organs, they need to undergo regulated cell death to prevent ongoing inflammation. Failure to do so can lead to progressive joint damage and prevent tissue healing, such as the case in RA joints. Therefore, we believe strategies that can reduce neutrophil numbers specifically within the inflamed joints will alleviate arthritis and minimise joint destruction. We confirmed that inflammatory signals can extend the survival of neutrophils. We also found that this is mediated by specific cell survival protein called BCL-XL. We found that blocking the pro-survival molecule BCL-XL can prevent the development of severe arthritis in a preclinical arthritis model. Specifically, BCL-XL antagonist (a drug that blocks BCL-XL) significantly reduces joint neutrophil numbers without affecting neutrophils in other organs. These results demonstrate the therapeutic potential of BCL-XL antagonist in inflammatory joint diseases without compromising immune cells in other organs. Given the preclinical nature of this project, the findings have not benefitted patients with musculoskeletal disease. However, results from these studies are encouraging, paving the way towards further proof-of-principle studies and clinical trials. We have revealed BCL-XL as a mechanism by which inflammatory cells (i.e. neutrophils) persist in inflamed organs and propagate tissue destruction. Subsequently, we also show that blocking this survival node with BCL-XL antagonist not only prevents the development of severe inflammation in arthritis model, but also other inflammatory settings such as sepsis and lung inflammation. These results suggest that BCL-XL antagonists may be therapeutically applicable in many other debilitating inflammatory diseases driven by neutrophils, including sepsis, chronic obstructive pulmonary disease and gout. In a small set of experiments, the BCL-XL antagonist could also kill inflammatory neutrophils taken from the inflamed joints of arthritis patients. This confirms the clinical efficacy and supports the therapeutic potential of BCL-XL antagonist to treat several human diseases. Another known effect of BCL-XL antagonists is their propensity to reduce platelet numbers (thrombocytopenia). This is because platelets, tiny cell fragments responsible for blood clotting, require BCL-XL to survive. While this condition may be a concern and a preference would be to prevent drug-induced thrombocytopenia altogether, having reduced number of platelets may in fact offer an additional therapeutic benefit in chronic inflammatory syndromes. Our future research is focused on developing new BCL-XL antagonists that spare platelets and examine whether they similarly block inflammatory arthritis and if they can be applied to other inflammatory diseases where therapeutic options remain limited.