Systemic cytokine profiling enhances the performance of dd-cfDNA to detect cardiac rejection

The association between circulating cytokines and allograft injury due to allograft rejection (AR) remains poorly defined. We hypothesize that cytokines correlate with the degree of allograft injury during AR. This case-control study measured cytokines and cell-free DNA in 88 heart transplant plasma samples (54 AR, 34 non-rejecting (NR) controls) and 26 healthy controls. AR patients exhibited higher levels of total and percent donor-derived cfDNA (%dd-cfDNA) and proinflammatory cytokines, and lower levels of type II cytokines/chemokines and Th17/23 axis cytokines compared to NR or HCs. The cfDNA levels positively correlated with proinflammatory cytokines and negatively with MDC and cytokines of the Th17/IL-23 axis. A Lasso regression model combining cytokines and %dd-cfDNA (AUC = 0.93) showed better AR diagnostic performance than either cytokines or %dd-cfDNA alone. The study concluded that inflammatory and regulatory cytokine levels correlate with allograft injury, and combining cytokines with %dd-cfDNA may enhance AR detection.