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Etude des relations pharmacodynamiques, pharmacogénétiques et pharmacocinétiques des immunosuppresseurs anticalcineurines chez les transplantés hépatiques

Abstract : Calcineurin inhibitors (CNI) are the immunosuppressants most employed in solid organ transplantation, despite their toxicity and suboptimal efficacy. Their effects show huge intra and inter-individual variability, not explained by differences in drug doses, concentrations or areas under the concentration -time curve, limiting the benefits of therapeutic drug monitoring and pointing that other factors contribute to response variability. No single biomarker currently available meets all the ideal requirements, i.e. non-invasiveness, reliability, sensitivity, specificity, reproducibility, and short turnaround time. To search for suitable PD biomarkers, i.e., with high specificity for calcineurin inhibition and most affected by inter-individual variability ,our works aimed at exploring the pharmacodynamics(PD) of CNI, the strength and variability of signal translation along the calcineurin pathway, as well as the steps where sources of internal (genetic) or external variability are the most influential .Our main results in healthy volunteers’ PBMC ex vivo showed : that the inhibition of NFAT1 in PBMC nuclei and of IL-2 and CD25 expression in different subsets of T lymphocytes followed I/Imax models; that IL-2 and CD25 responses to NFAT inhibition fitted and allosteric sigmoid model; and that several polymorphisms in genes involved in CNI PD participated in the inter-individual variability of these biomarkers. In patients on the waiting list of liver transplantation we were able: to measure CNI PD biomarkers before as well as after ex-vivo stimulation; to report PG/PD relationships, as well as PD/PD interactions within the pathway. In liver transplant recipients, those on cyclosporine showed more inter -individual PD variability than those on tacrolimus and different regulations within the pathway. In summary, IL-2 and CD25 in CD8+ T cells and CD25 in CD4+ T cells may be reliable biomarkers of CNI activity, with the largest inter-individual variability. Moreover , clinical cases suggest that NFAT1 levels in PBMC nuclei might help to anticipate infection episodes, while Tregs diminution and high levels of IL-2 expression in CD8+ T cells might predict acute cellular rejection.
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Ofelia Noceti Penza. Etude des relations pharmacodynamiques, pharmacogénétiques et pharmacocinétiques des immunosuppresseurs anticalcineurines chez les transplantés hépatiques. Médecine humaine et pathologie. Université de Limoges, 2015. Français. ⟨NNT : 2015LIMO0023⟩. ⟨tel-01555730⟩

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