Immune and gene expression profiling during tacrolimus to everolimus conversion early after liver transplantation

Abstract

Early elimination of tacrolimus in favor of everolimus can improve renal function in liver transplant recipients. However, as this approach increases the risk of acute rejection, it may benefit from predictive biomarkers guiding weaning. We enrolled 20 recipients on stable tacrolimus + everolimus to undergo tacrolimus withdrawal early post-liver transplant. Blood samples were collected at month 3 (withdrawal initiation), 4 (withdrawal completion), 4.5 and 6 (both everolimus alone). 15 patients did not reject and 5 had mild rejection responding to tacrolimus resumption. Before tacrolimus withdrawal, eventual rejecters had higher percentages of CD56⁺ NK cells and CD19⁺CD27⁺CD24⁺ memory B cells, and lower levels of T cells expressing the exhaustion marker PD-1. Over time, memory B cells, Ki-67⁺CD3⁺ (proliferating) cells and CD4⁺CD127^-CD25^HIGH FOXP3⁺ Tregs increased in rejecters. Tregs also increased in non-rejecters over time. The number of differentially expressed genes progressively increased in rejecters, particularly in mTOR, Eukaryotic Initiation Factor 2, and Neuroinflammation signaling pathways. There was no difference in anti-HLA antibodies between the groups. In summary, blood mononuclear cell and gene expression may predict successful vs. failed early tacrolimus withdrawal in liver transplant recipients. While needing validation, these preliminary findings highlight the potential for cellular and molecular biomarkers to guide decision-making during tacrolimus weaning.

Keywords: Acute rejection; Biomarker; Immunosuppression minimization; Treg; mTOR inhibitor.