References of "Beguin, Yves"
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See detailThe clinical relevance of imatinib plasma trough concentrations in chronic myeloid leukemia. A Belgian study
Van Obbergh, F; Knoops, L; Devos, T et al

in Clinical Biochemistry (in press)

This retrospectivemulticenter study in patientswith chronic myeloid leukemia in chronic phasewas undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice ... [more ▼]

This retrospectivemulticenter study in patientswith chronic myeloid leukemia in chronic phasewas undertaken to confirm the clinical relevance of imatinib plasma concentrations monitoring in daily practice. Forty-one patients, with 47 imatinib plasma measurements, were analyzed during treatment with imatinib given at a fixed 400mg daily dose. A significant inverse relationship of imatinib concentration with the patients' weight was observed (Pearson's test: p=0.02,R2=0.1). More interestingly, patientswith poor response (switched to another tyrosine kinase inhibitor because of imatinib failure, or because of disease progression after an initial response) displayed a significantly lower mean imatinib concentration as compared to patients maintained on imatinib (822 ng/mL vs 1099 ng/mL; Student's t-test, p=0.04). Failure or disease progression occurred more often in patients in the lowest quartile of imatinib concentrations compared to patients in the highest quartile (p = 0.02, logrank test). No correlation could be established with other biological or clinical parameter, including complete cytogenic response and majormolecular response. In conclusion: in patients treatedwith imatinib at a fixed daily dose of 400 mg, imatinib plasma concentrations decreased with increasing body weight and were lower in patients switched to another tyrosine kinase inhibitor due to imatinib failure. Systematic determination of imatinib plasma trough levels should be encouraged in such patients. [less ▲]

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See detailOutcome after failure of allogeneic hematopoietic stem cell transplantation in children with acute leukemia: a study by the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC)
Rorhlich; Roux, C; Tifratene, K et al

in Bone Marrow Transplantation (in press)

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in case of post-transplantation ... [more ▼]

Allogeneic hematopoietic stem cell transplantation (SCT) contributes to improved outcome in childhood acute leukemia (AL). However, therapeutic options are poorly defined in case of post-transplantation relapse. We aimed to compare treatment strategies in 334 consecutive children with acute leukemia relapse or progression after SCT in a recent ten-year period. Data could be analyzed in 288 patients (157 ALL, 123 AML and 8 biphenotypic AL) with a median age of 8.16 years at transplantation. The median delay from first SCT to relapse or progression was 182 days. The treatment consisted in chemotherapy alone (n=108), chemotherapy followed by second SCT (n=70), supportive/palliative care (n=67), combination of chemotherapy and DLI (n=30), or isolated reinfusion of donor lymphocytes (DLI) (n=13). The median OS duration after relapse was 164 days and differed according to therapy: DLI after chemotherapy = 385 d, second allograft = 391d, chemotherapy = 174d, DLI alone = 140d, palliative care = 43d. A second SCT or a combination of chemotherapy and donor lymphocytes infusion yielded similar outcome (HR=0.85, p=0.53) unlike chemotherapy alone (HR 1.43 p=0.04), palliative care (HR=4.24, p<0.0001) or isolated DLI (HR=1,94, p<0.04). Despite limitations in this retrospective setting, strategies including immunointervention appear superior to other approaches, mostly in AML. [less ▲]

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See detailFocus sur les lymphocytes T dans la maladie du greffon contre l'hôte après allogreffe de cellules soucges hématopoïétiques: implications pour de nouvelles stratégies de prévention
Vrancken, L; Delens, Loïc ULg; BEGUIN, Yves ULg et al

in Oncol. Hematol. (in press)

Malgré les stratégies de prévention actuelles, la maladie du greffon contre l’hôte (greffe-versus-hôte, GVH) aiguë (GVHa) reste une complication sévère et fréquente de l’allogreffe de cellules souches ... [more ▼]

Malgré les stratégies de prévention actuelles, la maladie du greffon contre l’hôte (greffe-versus-hôte, GVH) aiguë (GVHa) reste une complication sévère et fréquente de l’allogreffe de cellules souches hématopoïétiques. Bien que la physiopathologie de celle-ci ne reste que partiellement élucidée à ce jour, il est classiquement admis que les lymphocytes T (LT) jouent un rôle important dans son processus biologique. Les progrès récents de l’immunologie des LT dans la GVHa ont permis de diversifier les pistes visant à prévenir la survenue de cette complication post-greffe. Plusieurs approches sont en cours d’exploration dans des essais cliniques avec des résultats encourageant tels que la manipulation ex vivo des LT avant leur transfert chez le patient afin de leur faire exprimer des gènes suicide, l’élimination in vivo des LT proliférant directement après la greffe, l’inhibition de l’activation des LT en interférant avec les voies de signalisation en aval du TCR ou celles induites par les cytokines, l’induction de l’anergie des LT en bloquant les signaux de costimulation, le blocage de l’adressage des LT vers les organes lymphoïdes secondaires et les tissus cibles, la promotion de l’immunotolérance par la perfusion de lymphocytes T régulateurs ou par l’utilisation d’agents favorisant leur différenciation et leurs fonctions in vivo et la modulation de l’expression génique des cellules immunitaires par des modulateurs épigénétiques. Outre la prévention de la GVHa, le défi des nouvelles stratégies consiste également à ne pas compromettre l’effet bénéfique de la greffe contre la tumeur ni la reconstitution des défenses anti-infectieuses. [less ▲]

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See detailThe use of mesenchymal stromal cells in solid organ transplantation
GREGOIRE, Céline ULg; DETRY, Olivier ULg; Jouret, François ULg et al

in The Biology and Therapeutic Applications of Mesenchymal Cells (in press)

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See detailImmunomodulatory effects of rapamycin in xenogeneic Graft versus Host Disease
Ehx, Grégory ULg; Hannon, Muriel ULg; DUBOIS, Sophie ULg et al

in Biology of Blood and Marrow Transplantation (2017, March), 23(3), 365366

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Several studies have suggested that rapamycin (RAPA), an mTOR ... [more ▼]

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Several studies have suggested that rapamycin (RAPA), an mTOR inhibitor with immunosuppressive properties, may reduce GVHD severity and mortality, possibly by promoting regulatory T cells (Tregs). However, few data have been reported about the impact of this drug on overall T cell population. The present work aims at investigating the mechanisms by which RAPA impacts GVHD in a humanized mouse model of GVHD (NSG mice infused with human PBMCs). We observed that RAPA injections significantly reduced xenogeneic GVHD lethality and severity. RAPA dramatically reduced human cells chimerism in RAPA mice and increased CD4+/CD8+ T cells balance due to a lower proliferation of CD8+ T cells. In addition, the frequencies of naive CD4+ and CD8+ T cells were higher and the CD4+ T cells showed a reduced effector phenotype (CD45RO+CD27-). Further, the differentiation of helper T cells (Th1, Th2 and Th17) was significantly decreased in treated mice. Tregs were positively affected as RAPA up-regulated their expression of BCL-2 and KI67 as well as their STAT5 phosphorylation level, leading to higher Treg frequency in treated mice. Altogether these data suggest that RAPA ameliorates GVHD by lowering cytotoxic and effector CD4+ T cells frequency as well as promoting Tregs. [less ▲]

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See detailComparison of xenogeneic graft-versus-host reactions in humanized NSG and NSG-HLA-A2/HHD mice
Ehx, Grégory ULg; SOMJA, Joan ULg; Fransolet, Gilles ULg et al

Poster (2017, February 10)

Background. Infusion of regulatory T cells (Tregs) is currently investigated in patients with graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation as well as in solid ... [more ▼]

Background. Infusion of regulatory T cells (Tregs) is currently investigated in patients with graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation as well as in solid organ transplant recipients. The in vivo efficacy of various human Treg products (naïve Tregs, memory Tregs, ex vivo activated Tregs, …) is currently assessed in NSG mice. Specifically, injection of human peripheral blood mononuclear cells (PBMC) in NSG mice induces a xenogeneic GVHD (xGVHD) syndrome that can be prevented by Treg infusion. However, this model is somewhat limited by the fact that the immunologic reaction of human PBMC is directed exclusively towards murine antigens. Aim. In this report, we compared xGVHD induced by injection of human PBMCs in NSG and in NSG mice expressing the HDD construct designed for the expression of human HLA-A0201 convalently bound to human 2 microglobuline, enabling the expression of both HLA-A2 and 2 microglobuline. Methods. NSG and NSG-HLA-A2/HHD (NSG-HLA) mice were transplanted with either HLA-A2+ or HLA-A2− human PBMCs from healthy donors. In 3 independent experiments (3 different HLA-A2+/A2− donor pairs were used, n=86), survival and xGVHD scores were monitored for the remaining days of the experiments and in a fourth experiment mice were sacrificed at day 14 to perform various analyzes on their organs. Results. NSG-HLA mice presented overall lower survival rates and higher xGVHD scores than NSG mice (median survival: 28 vs 21 days, p<0.0001). Survival difference between NSG and NSG-HLA mice was higher when they were transplanted with HLA-A2− than with HLA-A2+ donors (HLA-A2−, median survival: 35 vs 25 days, p=0.0001; HLA-A2+, median survival: 23 vs 19 days, p=0.001). Blood platelet levels, as surrogate marker of hematopoiesis activity, were reduced in NSG-HLA mice in comparison with NSG mice at day 14, suggesting higher hematopoietic hypoplasia in the NSG-HLA mice. Flow cytometry experiments showed higher human CD45+ cells engraftment in NSG-HLA mice in blood, spleen, bone marrow, lungs and liver. Further, lower CD4+/CD8+ T cells ratio were observed in these organs in NSG-HLA mice, highlighting a higher frequency of cytotoxic T cells. These differences of engraftment or ratio could not be attributed to proliferation or activation differences since no variation of either KI67 or HLA-DR were observed between the two mouse models. Supporting the promotion of cytotoxic T cells in NSG-HLA mice, lower frequency of CD45RA+ and higher frequency of TNF-α+ among CD8+ T cells were observed in these animals in comparison with NSG mice. Finally, preliminary results suggest a specific cytotoxicity toward HLA-A2+ cells in NSG-HLA mice. Conclusion. NSG-HLA-A2/HHD mice develop more severe xGVHD than NSG, characterized by a higher human cell engraftment and higher frequency of cytotoxic T cells, probably reacting specifically toward human HLA-A2 antigen. Therefore these mice may be a better model to study human acute GVHD. [less ▲]

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See detailComparison of xenogeneic graft-versus-host reactions in humanized NSG and NSG-HLA-A2/HHD mice
Ehx, Grégory ULg; SOMJA, Joan ULg; Delens, Loïc ULg et al

Conference (2017, February 01)

Background. So far, the most commonly used mouse model of xenogeneic GVHD is NSG mice injected with human peripheral blood mononuclear cells (PBMCs). However, this model is somewhat limited by the fact ... [more ▼]

Background. So far, the most commonly used mouse model of xenogeneic GVHD is NSG mice injected with human peripheral blood mononuclear cells (PBMCs). However, this model is somewhat limited by the fact that the immunologic reaction of human PBMC is directed exclusively towards murine antigens. Aim. Here, we compared xGVHD induced by injection of human PBMCs in NSG and in NSG mice expressing the HDD construct designed for the expression of human HLA-A0201 convalently bound to human b2 microglobuline, enabling the expression of both HLA-A2 and b2 microglobuline. Methods. NSG and NSG-HLA-A2/HHD (NSG-HLA) mice were transplanted with either HLA-A2+ or HLA-A2− human PBMCs from healthy donors. Survival and xGVHD scores were monitored for the remaining days of the experiments or mice were sacrificed at day 14 to perform various analyzes on their organs. Results. NSG-HLA mice presented overall lower survival rates and higher xGVHD scores than NSG mice (median survival: 28 vs 21 days, p<0.0001). Survival difference between NSG and NSG-HLA mice was higher when they were transplanted with HLA-A2− than with HLA-A2+ donors (HLA-A2−, median survival: 35 vs 25 days, p=0.0001; HLA-A2+, median survival: 23 vs 19 days, p=0.001). Flow cytometry experiments showed higher human CD45+ cells engraftment in NSG-HLA mice in blood, spleen, bone marrow, lungs and liver. Further, lower CD4+/CD8+ T cells ratio were observed in these organs in NSG-HLA mice, highlighting a higher frequency of cytotoxic T cells. These differences of engraftment or ratio could not be attributed to proliferation or activation differences since no variation of either KI67 or HLA-DR were observed between the two mouse models. Supporting the promotion of cytotoxic T cells in NSG-HLA mice, lower frequency of CD45RA+ and higher frequency of TNF-α+ among CD8+ T cells were observed in NSG-HLA in comparison with NSG mice. Finally, preliminary results suggest a specific cytotoxicity toward HLA-A2+ cells in NSG-HLA mice. Conclusion. NSG-HLA-A2/HHD mice develop more severe xGVHD than NSG, characterized by a higher human cell engraftment and higher frequency of cytotoxic T cells, probably reacting specifically toward human HLA-A2 antigen. Therefore these mice may be a better model to study human acute GVHD. [less ▲]

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See detailMultiple myeloma bone disease: from mechanisms to next generation therapy
Heusschen, Roy ULg; Muller, Joséphine ULg; WITHOFS, Nadia ULg et al

in Belgian Journal of Hematology (2017)

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See detailGenomic Studies of Multiple Myeloma Reveal an Association between X Chromosome Alterations and Genomic Profile Complexity.
Sticca, Tiberio ULg; CABERG, Jean-Hubert ULg; Wenric, Stéphane ULg et al

in Genes, Chromosomes & Cancer (2017), 56

The genomic profile of multiple myeloma (MM) has prognostic value by dividing patients into a good prognosis hyperdiploid group and a bad prognosis non-hyperdiploid group with a higher incidence of IgH ... [more ▼]

The genomic profile of multiple myeloma (MM) has prognostic value by dividing patients into a good prognosis hyperdiploid group and a bad prognosis non-hyperdiploid group with a higher incidence of IgH translocations. This classification, however, is inadequate and many other parameters like mutations, epigenetic modifications and genomic heterogeneity may influence the prognosis. We performed a genomic study by array-based comparative genomic hybridization (aCGH) on a cohort of 162 patients to evaluate the frequency of genomic gains and losses. We identified a high frequency of X chromosome alterations leading to partial Xq duplication, often associated with Xi deletion in female patients. This partial X duplication could be a cytogenetic marker of aneuploidy as it is correlated with a high number of chromosomal breakages. Patient with high level of chromosomal breakage had reduced survival regardless the region implicated. A higher transcriptional level was shown for genes with potential implication in cancer and located in this altered region. Among these genes, IKBKG and IRAK1 are members of the NFKB pathway which plays an important role in MM and is a target for specific treatments. [less ▲]

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See detailFactors associated with self-perceived burden to the primary caregiver in older patients with hematologic malignancies: an exploratory study
Libert, Y; Borghgraef, C; BEGUIN, Yves ULg et al

in Psycho-oncology (2017), 10

Objective: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of ... [more ▼]

Objective: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of selfperceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. Methods: In total, 166 consecutive patients with hematologic malignancies aged ≥65 years were recruited at the time of chemotherapy initiation. Patients’ SPB-PC was assessed using a 100-mm visual analogue scale (VAS). Characteristics potentially associated with SPB-PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients’/primary caregivers’ personal relationship characteristics (family tie, support), were assessed. Results: Thirty-five percent of patients reported moderate to severe SPB-PC (VAS ≥ 50 mm). Patients’ SPB-PC was associated with lower Karnofsky performance (β = 0.135, p = 0.058) and ADL (β = 0.148, p = 0.037) scores, and higher HADS (β = 0.283, p<0.001) and FACT-Cog perceived cognitive impairments subscale (β = 0.211, p = 0.004) scores. The proportion of explained variance was 23.5%. Conclusions: Health care professionals should be aware that about one third of older cancer patients experience moderate to severe SPB-PC at the time of chemotherapy initiation. They should adapt their support of patients who report such a feeling. [less ▲]

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See detailMesenchymal stromal cell therapy for inflmmatory bowel diseases
GREGOIRE, Céline ULg; LECHANTEUR, Chantal ULg; BRIQUET, Alexandra ULg et al

in Alimentary Pharmacology & Therapeutics (2017), 45

Background Inflammatory bowel diseases (IBD) are chronic relapsing diseases in which pro-inflammatory immune cells and cytokines induce intestinal tissue damage and disability. Mesenchymal stromal cells ... [more ▼]

Background Inflammatory bowel diseases (IBD) are chronic relapsing diseases in which pro-inflammatory immune cells and cytokines induce intestinal tissue damage and disability. Mesenchymal stromal cells (MSCs) exert powerful immunomodulatory effects and stimulate tissue repair. Aim To review the current data on mesenchymal stromal cell therapy in IBD. Method We searched PubMed and ‘ClinicalTrials.gov’ databases using the terms ‘mesenchymal stromal cells’, ‘mesenchymal stem cell transplantation’, ‘inflammatory bowel diseases’, ‘Crohn disease’ and ‘colitis, ulcerative’. Additional publications were identified from individual article reference lists. Results MSCs include inhibition of Th1/Th17 lymphocytes and recruitment of regulatory T lymphocytes, induction of antigen-presenting cells into a regulatorylike profile, and stimulation of epithelial cell differentiation and proliferation. More than 200 patients with refractory fistulas have been treated with local injections of MSCs, resulting in complete response in more than half, and in overall response in approximately two thirds of patients. In refractory luminal Crohn’s disease, 49 cases of systemic MSC infusions have been reported, while trials with autologous MSCs resulted in mitigated responses, studies using allogeneic MSCs were promising, with around 60% of patients experiencing a response and around 40% achieving clinical remission. Conclusions Mesenchymal stromal cells might represent a promising therapy for IBD, especially for Crohn’s disease. There remain many unsolved questions concerning the optimal origin and source of mesenchymal stromal cells, dosage and modalities of administration. Moreover, mesenchymal stromal cells still need to prove their effectiveness compared with conventional treatments in randomised controlled trials. [less ▲]

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See detailThe role of mesenchymal stem cells in the treatment of ulcerative colitis and Crohn's disease
GREGOIRE, Céline ULg; Louis, Edouard ULg; BRIQUET, Alexandra ULg et al

in Atkinson, K; Ed (Eds.) The Biology and Therapeutic Applications of Mesenchymal Cells (2017)

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See detailA surprising and dramatic neuroendocrine-immune phenotype of mice deficient in Growth Hormone-Releasing Hormone (GHRH)
Farhat, Khalil; Bodart, Gwennaelle; Martens, Henri ULg et al

in Neuroimmunomodulation (2017)

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See detailAllogeneic stem cell transplantation for patients with myelodysplastic syndrome 70 years of age or older: A retrospective study of the MDS subcommittee of the Chronic Malignancies Working Party (CMWP) of the EBMT
Heidenreich, S; Ziagkos, D; De Wreede, L et al

in Biology of Blood & Marrow Transplantation (2017), 23

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n ... [more ▼]

In this retrospective analysis we evaluated the outcome of 313 patients aged ≥ 70 years in the registry of the European Group for Blood and Marrow Transplantation with myelodysplastic syndrome (MDS; n = 221) and secondary acute myeloid leukemia (n = 92) who underwent allogeneic hematopoietic stem cell transplantation (HSCT) from related (n = 79) or unrelated (n = 234) donors. Median age at HSCT was 72 years (range, 70 to 78). Conditioning regimen was nonmyeloablative (n = 54), reduced intensity (n = 207), or standard intensity (n = 52). Allogeneic HSCT for MDS patients ≥ 70 years was increasingly performed over time. Although during 2000 to 2004 only 16 patients received HSCT, during 2011 to 2013 the number of transplantations increased to 181. The cumulative incidence of nonrelapse mortality at 1 year and relapse at 3 years was 32% and 28%, respectively, with a 3-year overall survival rate of 34%. Good performance, determined by Karnofsky performance status, and recipients’ seronegativity for cytomegalovirus was associated with 3-year estimated overall survival rates of 43% (P = .01) and 46% (P = .002), respectively. Conditioning intensity did not impact survival. After careful patient selection, allogeneic HSCT can be offered to patients older than 70 years with MDS. [less ▲]

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See detailLimited Impact of Imatinib in a Murine Model of Sclerodermatouc Chronic Graft-versus-Host Disease
Belle, Ludovic ULg; Fransolet, Gilles ULg; Somja, Joan ULg et al

in PLoS ONE (2016), 11

Background Sclerodermatous chronic Graft-versus-Host Disease (scl-cGVHD) is one of the most severe form of cGVHD. The Platelet-derived Grotwth Factor (PDGF) and the Transforming Growth Factor-β (TGF-β ... [more ▼]

Background Sclerodermatous chronic Graft-versus-Host Disease (scl-cGVHD) is one of the most severe form of cGVHD. The Platelet-derived Grotwth Factor (PDGF) and the Transforming Growth Factor-β (TGF-β) play a significant role in the fibrosing process occurring in scl-cGVHD. This prompted us to assess the impact of the PDGF-r and c-Abl tyrosine kinase inhibitor imatinib on scl-cGVHD. Methods To assess the impact of imatinib on T cell subset proliferation in vivo, Balb/cJ recipient mice were lethally (7 Gy) irradiated and then injected with 10x106 bone marrow cells from B10.D2 mice on day 0. Fourteen days later, 70x106 carboxyfluorescein succinimidyl ester (CFSE)-labeled splenocytes from B10.D2 mice were infused and imatinib or sterile water was administered for 5 days. To induce severe scl-cGVHD, Balb/cJ mice were injected i.v. with 10.106 bone marrow cells and 70.106 splenocytes from B10.D2 donor mice after 7 Gy irradiation. Mice were then given sterile water or imatinib from day +7 after transplantation to the end of the experiment (day +52). Results Imatinib decreased the proliferation of total T cells (P = 0.02), CD8+ T cells (P = 0.01), and of regulatory T cells (Tregs) (P = 0.02) in the spleen. In the severe scl-cGVHD model, imatinib-treated mice had significantly lower levels of PDGF-r phosphorylation than control mice on day 29 after transplantation (P = 0.008). However, scl-cGVHD scores were similar between vehicle- and imatinib-treated mice during the whole experiment, while there was a suggestion for less weight loss in imatinib-treated mice that reached statistical significance at day +52 following transplantation (P = 0.02). [less ▲]

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See detailXenogeneic graft-versus-host disease: Impact of Th17 cells.
Delens, Loïc ULg; SERVAIS, Sophie ULg; Vrancken, Louise et al

Poster (2016, December 08)

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See detailLimited impact of imatinib in a murine model of sclerodermatous chronic graft-versus-host disease (scl-cGVHD)
Fransolet, Gilles ULg; Belle, Ludovic; SOMJA, Joan ULg et al

Conference (2016, December 08)

- Introduction: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD ... [more ▼]

- Introduction: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD develop the sclerodermatous form of the disease characterized by multiple organ fibrosis and loss of skin elasticity. Several studies have shown the potential benefits of imatinib, a tyrosine kinase inhibitor (TKI), as a treatment of fibrosis in cGVHD due to its ability to inhibit simultaneously PDGF-R and c-Abl pathways which are both involved in fibrosis mechanisms. - Aims: Some early-phase clinical studies have assessed the impact of TKIs in patients with steroid-refractory cGVHD. Unfortunately, these studies yielded to conflicting results underlying the importance of re-assessing the impact of imatinib in scl-cGVHD pre-clinical models. This work investigates the possible benefits of imatinib on fibrosis in a murine model of sclerodermatous chronic GVHD (scl-cGVHD). - Methods and results: Lethally irradiated Balb/cJ mice (7 Gy TBI) were injected i.v. with 1.106 or 10.106 bone marrow cells and 2.106 or 70.106 splenocytes from B10.D2 donnor mice (Moderate and Classical scl-cGVHD models respectively). Mice were then treated with sterile water or imatinib (150 mg/kg/day) by oral gavage from day +7 to day +52 following transplantation. cGVHD severity was assessed three times/week with a scoring system encompassing 5 criteria (mice posture, weight loss, activity, hair loss, skin integrity ; 0-1-2 point(s)/criteria). Skin biopsies were performed on day +29 following transplantation to assess phosphorylation of c-Abl (TGF-β pathway) and PDGF receptor. Our results show that imatinib failed to prevent/improve GVHD with a similar evolution of the GVHD severity with no differences between groups (neither in moderate cGVHD model, nor in the classical cGVHD model). Mice weight loss during the experiments was also comparable between groups in both models of cGVHD. In the classical model, histological analyses indicate a significant reduction of the phosphorylation level of the PDGR receptor (p = 0.0079). In vivo cell proliferation assay with CFSE were also performed and showed a reduced proliferation of T cells and subsets (CD4, CD8 and Tregs) in spleen, lymph nodes, bone marrow and blood after imatinib treatment. Finally, FACS analyses performed on days +21 and +35 after transplantation did not show any differences in the absolute T-cell counts. - Conclusions: Although we have observed a decreased phosphorylation level of PDGR receptor and less proliferation of T cells and subsets in vivo, imatinib failed to alleviate scl-cGVHD both in moderate and classical murine models of scl-cGVHD. [less ▲]

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See detailAzacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects
Ehx, Grégory ULg; Fransolet, Gilles ULg; de Leval, Laurence ULg et al

Conference (2016, November 18)

The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading ... [more ▼]

The demethylating agent 5-azacytidine (AZA) has proven its efficacy as treatment for myelodysplastic syndrome and acute myeloid leukemia. In addition, AZA can demethylate FOXP3 intron 1 (FOXP3i1) leading to the generation of regulatory T cells (Treg). Here, we investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) and graft-versus-leukemia effects in a humanized murine model of transplantation (human PBMCs-infused NSG mice), and described the impact of the drug on human T cells in vivo. We observed that AZA improved both survival and xGVHD scores. Further, AZA significantly decreased human T-cell proliferation as well as IFN-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA significantly increased Treg frequency through hypomethylation of FOXP3i1 as well as increased Treg proliferation. The later was subsequent to higher STAT5 signaling in Treg from AZA-treated mice, which resulted from higher IL-2 secretion by conventional T cells from AZA-treated mice itself secondary to demethylation of the IL-2 gene promoter by AZA. Importantly, Tregs harvested from AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Finally, graft-versus-leukemia effects (assessed by growth inhibition of THP-1 cells, transfected to express the luciferase gene) were not abrogated by AZA. In summary, our data demonstrate that AZA prevents xGVHD without abrogating graft-versus-leukemia effects. These findings could serve of basis for further studies of GVHD prevention by AZA in acute myeloid leukemia patients offered an allogeneic transplantation. [less ▲]

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See detailLimited impact of imatinib in a murine model of sclerodermic chronic graft-versus-host disease
Belle, Ludovic; Fransolet, Gilles ULg; SOMJA, Joan ULg et al

Poster (2016, November 17)

Background: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD develop ... [more ▼]

Background: Graft-versus-host disease (GVHD) remains one of the major complications following haematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients with chronic GVHD develop the sclerodermatous form of the disease characterized by multiple organ fibrosis and loss of skin elasticity. Several studies have shown the potential benefits of imatinib, a tyrosine kinase inhibitor, as a treatment of fibrosis in cGVHD due to its ability to inhibit simultaneously PDGF-R and c-Abl pathways which are both involved in fibrosis mechanisms. This work investigates the possible benefits of imatinib on fibrosis in a murine model of sclerodermatous chronic GVHD (sclcGVHD). Methods: Lethally irradiated Balb/cJ mice (7 Gy TBI) were injected i.v. with 10.106 bone marrow cells and 70.106 splenocytes from B10.D2 donnor mice. Mice were then treated with sterile water or imatinib (150 mg/kg/day) by oral gavage from day +7 to day +52 following transplantation. GVHD severity was assessed three times/week with a scoring system encompassing 5 criteria (mice posture, weight loss, activity, hair loss, skin integrity ; 0-1-2 point(s)/criteria). Results: Our results show that imatinib failed to prevent/improve GVHD with a similar evolution of the GVHD severity with no differences between groups. Histological analyses indicate a significant reduction of the phosphorylation level of the PDGR receptor (p = 0,033) and a trend to a decreased level of phosphorylated c-Abl (p = 0,1854). In vivo cell proliferation assay with CFSE were also performed and showed a reduced proliferation of T cells and subsets (CD4, CD8 and Tregs) in spleen, lymph nodes, bone marrow and blood after imatinib treatment. Finally, FACS analyses performed on days +21 and +35 after transplantation did not show any differences in the absolute T-cell counts. Conclusion: Although we have observed a decreased phosphorylation level of PDGR receptor and less proliferation of T cells and subsets in vivo, imatinib failed to alleviate scl-cGVHD in a murine model of severe scl-cGVHD. [less ▲]

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