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

被引:11
作者
Millan, Olga [1 ,2 ]
Ruiz, Pablo [3 ]
Fortuna, Virginia [2 ]
Navasa, Miquel [1 ,3 ]
Brunet, Merce [1 ,2 ]
机构
[1] Inst Salud Carlos III, Biomed Res Ctr Hepat & Digest Dis CIBERehd, Madrid, Spain
[2] Univ Barcelona, Hosp Clin Barcelona, Pharmacol & Toxicol Biochem & Mol Genet, Biomed Diagnost Ctr CDB,IDIBAPS, Barcelona, Spain
[3] Univ Barcelona, Hosp Clin Barcelona, IDIBAPS, Liver Transplant Unit, Barcelona, Spain
关键词
calcineurin inhibitors; CMV; liver transplantation; NFAT-regulated gene expression; intralymphocytary cytokines; subclinical rejection; T cell-mediated acute rejection; REGULATED GENE-EXPRESSION; RENAL-ALLOGRAFT RECIPIENTS; CALCINEURIN INHIBITORS; CYCLOSPORINE-A; CYTOMEGALOVIRUS-INFECTION; TACROLIMUS THERAPY; IFN-GAMMA; NFAT; CONSENSUS; PERSPECTIVE;
D O I
10.1111/liv.14339
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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-gamma 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-gamma and GM-CSF and intralymphocytary synthesis of IL-2 and IFN-gamma 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-gamma and %CD4CD69IFN-gamma 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-gamma 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.
引用
收藏
页码:931 / 946
页数:16
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