Activity of the calcineurin pathway in patients on the liver transplantation waiting list: factors of variability and response to tacrolimus inhibition. Pierre Marquet Institutions and affiliations

Abstract : BACKGROUND: We sought to evaluate, in patients on a liver transplantation waiting list, potential biomarkers of the base calcineurin pathway activity with use of a new model of nonstimulated peripheral blood mononuclear cells (PBMC) and ex vivo response to tacrolimus (TAC). METHODS: The calcineurin pathway activity was explored ex vivo in stimulated and nonstimulated PBMC from 19 patients. The inhibition of NFATC1+ translocation to PBMC, expression of intracellular IL-2, and membrane CD25 in different T-cell subsets were measured by multiparametric flow cytometry before and after exposure to TAC. We also studied the influence on the individual response of polymorphisms in 3 key genes of the calcineurin pathway: PPIA, PPP3CA, and IL2RA. RESULTS: All pharmacodynamics profiles closely fitted an I/Imax sigmoid model. Interindividual variability was higher in nonstimulated than in stimulated conditions, as well as in the presence of TAC. IL-2+CD8+ cells at TAC Imax showed the highest interindividual variability, suggesting its usefulness as a biomarker of individual TAC effects integrating many different sources of regulation and variability. Moreover, in the absence of TAC, patients with end-stage liver disease exhibited lower NFATC1 translocation and T-cell activation than healthy volunteers from a previous study under similar conditions. Multivariate statistical analysis showed strong and significant associations between TAC pharmacodynamic parameters and 2 polymorphisms in the gene-coding cyclophilin A (rs8177826 and rs6850). CONCLUSIONS: We show the feasibility of using nonstimulated PBMCs to explore the calcineurin pathway under more physiologic conditions and point toward potential biomarkers for TAC pharmacodynamic monitoring.
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Clinical Chemistry, American Association for Clinical Chemistry, 2017, Epub ahead of print. 〈10.1373/clinchem.2017.272534〉
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Ofelia Noceti, Lucie Pouché, Patricia Esperón, Daniela Lens, Marcelo Vital, et al.. Activity of the calcineurin pathway in patients on the liver transplantation waiting list: factors of variability and response to tacrolimus inhibition. Pierre Marquet Institutions and affiliations. Clinical Chemistry, American Association for Clinical Chemistry, 2017, Epub ahead of print. 〈10.1373/clinchem.2017.272534〉. 〈inserm-01621448〉

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