Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List :  Factors of Variability and Response to Tacrolimus Inhibition

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Título

Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List :  Factors of Variability and Response to Tacrolimus Inhibition

Tema

HIGADO
TRANSPLANTE DE HIGADO
TACROLIMUS
BIBLIOGRAFIA NACIONAL QUIMICA
2017

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 NFAT1 translocation to PBMC nuclei, 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 NFAT1 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.

Autor

Noceti, Ofelia
Pouché, Lucie
Lens, Daniela
Vital, Marcelo
Touriño, Cristina
Gerona, Solange
Woillard, Jean Baptiste
Marquet, Pierre

Fuente

v. 63, no. 11, 2017. -- p. 1734-1744

Editor

American Association for Clinical Chemistry

Fecha

2017

Derechos

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PDF

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Tipo

Artículo

Identificador

DOI: 10.1373/clinchem.2017.272534

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PDF
Fecha de agregación
June 29, 2018
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Document
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Citación
Noceti, Ofelia, “Activity of the Calcineurin Pathway in Patients on the Liver Transplantation Waiting List : Factors of Variability and Response to Tacrolimus Inhibition,” RIQUIM - Repositorio Institucional de la Facultad de Química - UdelaR, accessed July 23, 2018, http://riquim.fq.edu.uy/items/show/4971.
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