Extracellular FKBP12 Inhibits Tacrolimus Translocation to Peripheral Blood Mononuclear Cells Reducing Immunosuppressive Effects: An In Vitro Study

BACKGROUND: Tacrolimus is an essential immunosuppressant drug used during transplantation; however, its blood concentration must be carefully managed. Recent evidence suggests that tacrolimus concentrations in peripheral blood mononuclear cells (PBMCs) better reflect immunosuppressive activity than whole blood concentrations. In this study, the authors investigated the effect of extracellular FK506-binding protein (FKBP)12, a high-affinity tacrolimus-binding protein, on tacrolimus-mediated T-cell suppression. METHODS: Human whole blood and purified PBMCs were stimulated with phytohemagglutinin-L to induce cytokine (interleukin-2, interferon-gamma) production. Tacrolimus accumulation in PBMCs was quantified using supercritical fluid chromatography-tandem mass spectrometry. RESULTS: Tacrolimus inhibited cytokine release in a concentration-dependent manner; however, extracellular FKBP12 significantly attenuated this effect. Extracellular FKBP12 reduced intracellular tacrolimus concentrations in a concentration-dependent manner, suggesting that extracellular FKBP12 binds tacrolimus, limiting its transfer into T cells and diminishing its immunosuppressive effect. CONCLUSIONS: The results underscore the potential impact of extracellular FKBP12 on tacrolimus pharmacodynamics and highlight the importance of monitoring PBMC tacrolimus concentrations and considering extracellular FKBP12 as a factor influencing drug distribution and efficacy. The study findings provide a novel perspective for refining therapeutic drug monitoring and advancing personalized immunosuppressive therapy in transplantation medicine.