A pre-emptive risk model for acute rejection in liver transplantation: an immunopharmacologic biomarker panel combining CD4+ T-cell profiling and tacrolimus exposure

Introduction Acute cellular rejection (ACR) is a T cell-driven event in liver transplantation. Current monitoring relies on detecting graft injury, lacking tools for pre-emptive risk assessment based on the patient’s real-time immune status. Methods We developed an immunopharmacologic risk model in a retrospective cohort of 98 liver transplant recipients (18 with biopsy-proven ACR). The model integrated peripheral CD4+ T-cell percentage (flow cytometry) and tacrolimus trough level. Firth-penalized logistic regression was used for model development, with internal validation via bootstrapping. Results The parsimonious model, comprising only CD4+ T-cell percentage and tacrolimus level, demonstrated good discrimination (AUC 0.774, 95% CI 0.674-0.874) and calibration. Critically, lead-time analysis revealed the model provided a median warning window of 8 days (IQR: 3.5 days) prior to biochemical injury onset. It offered significant incremental value over monitoring tacrolimus alone (AUC 0.774 vs. 0.694, ΔAUC=0.080, p=0.007) or CD4+ T cells alone (AUC 0.774 vs. 0.733, ΔAUC=0.041, p=0.014). Conclusion We identify and validate a novel, clinically actionable immunopharmacologic biomarker panel for ACR. This model enables pre-emptive risk stratification by capturing the high-risk confluence of immune activation and subtherapeutic immunosuppression, paving the way for personalized immunotherapy in transplant recipients.