Allograft and Recipient Tissue Injury during Cardiac Allograft Rejection: Evidence from Cell-free DNA

Cardiac allograft rejection (AR) is conventionally managed as an allograft disease. However, data in kidney transplant and pro-inflammatory cytokine studies suggest the occurrence of recipient tissue injury during AR, which to date remains poorly defined and is a recognized risk factor for poor survival. This study hypothesizes that AR is linked to recipient tissue injury, measured as plasma cell-free DNA (cfDNA), a biomarker of tissue injury. This study analyzed genetic and epigenetic signatures to quantify allograft and recipient cfDNA and the tissue sources for AR and stable controls. To provide a mechanistic connection, the study compared cfDNA damage-associated molecular pattern (DAMP) activity between AR and stable controls. Results indicate that both allograft and recipient cfDNA levels increase during AR compared to stable controls. The increased recipient cfDNA levels primarily originated from immune cells, vascular endothelium, hepatocytes, and kidney epithelial cells and correlated with conventional biomarkers of organ dysfunction. In cell culture models, AR-derived cfDNA demonstrated increased DAMP activity compared to cfDNA from stable controls. These findings suggest that AR is linked to heightened recipient cfDNA levels and an increased risk of recipient organ dysfunction. Future research is warranted to investigate these findings further towards improving the management and outcomes of AR.