Découverte de nouveaux marqueurs pharmacogénomiques de la maladie du greffon contre l'hôte en transplantation de cellules souches hématopoïétiques

Authors: Laverdière, Isabelle
Advisor: Guillemette, ChantalLévesque, Éric
Abstract: Hematopoietic stem cells transplantation (HSCT) is a potentially curative therapy for several hematological cancers such as leukemia. Following transplantation, effective immunosuppression prophylaxis is mandatory to prevent the graft-versus-host disease (GvHD) and improved the clinical outcome. However, GvHD still occurs in 25-50% of transplanted patient and is associated with high mortality rate. Optimization of immunosuppressive therapy is an easily modifiable factor that can improve the prognosis of patient after HSCT. In particular, polymorphisms of recipient and donor in genes with functions related to drugs transport, metabolism and action might influence the exposure and the efficacy of immunosuppressive therapy, and thus the clinical outcome. The evaluation of 20 candidate pharmacogenes in donor-recipient pairs of HSCT identified genetic polymorphisms associated with the risk of GvHD. Recipient genetic status for ABCC1 and ABCC2, related to methotrexate (MTX) transport, as well as polymorphisms in genes encoding molecular targets (ATIC and MTHFR) of this drug, exhibit a remarkable influence on acute GvHD prevalence. Similarly, the cyclosporin molecular target NFATc1 also increases the risk of GvHD. Importantly, the presence of ≥2 of these SNPs was found to be associated with high risk of developing severe grade of acute GvHD. In donor, we identified protective alleles in pathways related to transport (SLC19A1) and action (DHFR) of MTX. Conversely, NFATc2 enhances the risk of acute GvHD. To improve our understanding of the process behind these associations, we have an ongoing prospective study in HSCT. This innovative study will provide the opportunity to evaluate the influence of such genetic markers on the pharmacokinetic and pharmacodynamic of immunosuppressive drugs, as well as their relation with the risk of GvHD. For the specific needs of our study, we have developed two analytical methods based on mass spectrometry. The approaches we proposed in this thesis are complementary to conventional monitoring method and are promising tools to optimize drug therapy in HSCT. Identification of such biomarkers assessed before transplantation can help personalized patient care in order to prevent GvHD and improve survival.
Document Type: Thèse de doctorat
Issue Date: 2014
Open Access Date: 24 April 2018
Permalink: http://hdl.handle.net/20.500.11794/26966
Grantor: Université Laval
Collection:Thèses et mémoires

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