Nuclear factor of activated T cells as potential pharmacodynamic biomarker for the risk of acute and subclinical rejection in de novo liver recipients

Abstract Background & Aims Nuclear factor of activated T cell‐regulated gene expression (NFAT‐RGE) has been proposed as a pharmacodynamic biomarker for tacrolimus (Tac) and cyclosporine (CsA). Our aim was to evaluate the role of NFAT‐RGE in modulating intralymphocytary IL‐2 and IFN‐γ expression and its clinical utility as an early non‐invasive predictive biomarker for the risk of acute rejection (AR) and infection in de novo liver transplant (LT) recipients. Methods Fifty‐six LT recipients treated with Tac or CsA [with and without mycophenolate mofetil (MMF)] were included: 30 free of rejection or infection, 11 rejectors (T cell‐mediated acute rejection), 5 with subclinical rejection (SCR) and 10 with cytomegalovirus (CMV) infection. Within the first 3 months after transplantation, NFAT‐RGE of IL‐2, IFN‐γ and GM‐CSF and intralymphocytary synthesis of IL‐2 and IFN‐γ were evaluated by real‐time PCR and flow cytometry respectively. Results A significant increase in NFAT‐RGE was observed in patients who experienced TCMAR (75% [42–100%]) or SCR (41% [18–78%]) compared with patients without rejection or infection (14% [2–23%]). Positive correlations between the %NFAT‐RGE‐IFN and both the %CD8CD69IFN‐γ and %CD4CD69IFN‐γ and between the %NFAT‐RGE‐IL2 and the %CD8CD69IL2 were observed. NFAT‐RGE was significantly lower in CMV + patients than in non‐infected patients. Finally, an inverse correlation between the Tac or CsA concentration and inhibition of NFAT‐RGE were observed. Conclusions Sequential post‐transplantation NFAT‐RGE monitoring combined with intralymphocytary IL‐2 and IFN‐γ before transplantation and at the first and third month post‐transplantation may be key predictive and diagnostic biomarkers for the risk of TCMAR and SCR and better guide CNi therapy in LT patients.