First evidence for the role of the PD-1/PD-L1 pathway in the altered bone metabolism in periprosthetic joint infections and its potential for a targeted salvage therapy

• Applicant: Dr. Arne Kienzle
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 539915867

Despite increased use of antibiotics and improved surgical techniques, periprosthetic joint infections (PJI) occur in 1-5% of primary total arthroplasties. Addressing PJI and the resulting long-term complications is a growing need in an aging population with increasing demand for arthroplasty. PJI represents a devastating complication with high prosthesis failure rates due to recurrent PJI or aseptic loosening after mandatory revision surgery. The pathomechanism leading to prosthesis loosening is not well understood. Recently, we demonstrated significant upregulation in markers of inflammation in the bone in PJI. These changes towards an inflammatory environment in the bone are also linked to significant changes in the bone stock. Our results suggest that these changes persist despite guideline-compliant antimicrobial and surgical treatment. Myeloid derived suppressor cells (MDSCs) are activated during inflammation but are immunosuppressive. In a murine PJI model, MDSCs represented 50-75% of all leukocytes. In recent studies, their ability to differentiate into osteoclasts has been observed in autoimmune arthritis and cancer. Considering their relative population size in PJI and potential effects on bone metabolism via osteoclastic differentiation, we speculate MDSCs to be a viable target to prevent osteolysis in PJI. Dampening overshooting osteoclastogenesis may be a therapeutic approach to salvage compromised bone metabolism in PJI. Currently, bisphosphonate and RANKL inhibitor denosumab are commonly prescribed for osteoporosis. However, previous studies suggest increased risk for osteonecrosis and higher bacterial burden, limiting their usefulness in PJI. Programmed cell death 1 (PD-1) receptor is an immune regulatory receptor found on various cell populations of the immune system including MDSCs. Activation of MDSCs via the PD-1/PD-L1 pathway plays a key role in sepsis-induced immunosuppression. Additionally, recent advances suggest the PD-1 receptor to be linked to changes in bone volume. In contrast to bisphosphonates and denosumab, PD-1 inhibitors are safe to use in systemic infections and can limit progression of sepsis. We hypothesize that targeting PD-1 is a promising strategy to improve immunocompetence while suppressing excessive osteoclast generation and function. We aim to investigate the role of PD-1 in septic activation of MDSCs in PJI and the potential utility of PD-1 inhibitors as a salvage therapy to restore bone metabolism. In this project, plan to collect first evidence for the efficacy of targeting PD-1. The acquired data will be used to support the ongoing application for the Emmy Noether Program. This project will provide essential evidence needed for a potential use of anti-PD-1 therapy in PJI. This study and the resulting novel therapeutic approach will potentially benefit thousands of patients annually.

• DFG Programme: Research Grants