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See detailEccentric training for tendon healing after lesion: a rat model
Kaux, Jean-François ULg; Libertiaux, Vincent ULg; Leprince, Pierre ULg et al

in American Journal of Sports Medicine (in press)

BACKGROUND:The tendon is a dynamic entity that remodels permanently. Platelet-rich plasma (PRP) injection has been shown to have a beneficial effect on tendon healing after lesion in rats. Furthermore ... [more ▼]

BACKGROUND:The tendon is a dynamic entity that remodels permanently. Platelet-rich plasma (PRP) injection has been shown to have a beneficial effect on tendon healing after lesion in rats. Furthermore, eccentric exercise seems to improve the mechanical quality of the tendon. HYPOTHESIS:A combination of PRP injection and eccentric training might be more effective than either treatment alone. STUDY DESIGN:Controlled laboratory study. METHODS:Adult male rats were anesthetized, an incision was performed in the middle of their left patellar tendon and an injection of physiological fluid (PF) or homologous PRP was randomly made at the lesion level. The rats were then divided into 2 groups: the eccentric group, undergoing eccentric training 3 times a week, and the untrained group, without any training. Thus, 4 groups were compared. After 5 weeks, the tendons were removed and their ultimate tensile strength and energy were measured. Tendons were frozen for proteomic analyses when all biomechanical tests were completed. Statistical analysis was performed with linear mixed effect models. RESULTS:No significant difference was found between the treatments using PF injection or PRP injection alone. However, the value of the ultimate tensile force at rupture was increased by 4.5 N (108% of control, P = .006) when eccentric training was performed. An intragroup analysis revealed that eccentric training significantly improved the ultimate force values for the PRP group. Proteomic analysis revealed that eccentric training led to an increase in abundance of several cytoskeletal proteins in the PF group, while a decrease in abundance of enzymes of the glycolytic pathway occurred in the PRP treated groups, indicating that this treatment might redirect the exercise-driven metabolic plasticity of the tendon. CONCLUSION: Eccentric training altered the metabolic plasticity of tendon and led to an improvement of injured tendon resistance regardless of the treatment injected (PF or PRP). CLINICAL RELEVANCE:This study demonstrates the necessity of eccentric rehabilitation and training in cases of tendon lesion regardless of the treatment carried out. [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 et al

in Oncoimmunology (2017)

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 detailAccurate Control of 17beta-Estradiol Long-Term Release Increases Reliability and Reproducibility of Preclinical Animal Studies.
Gérard, Céline ULg; Gallez, Anne ULg; Dubois, Charline ULg et al

in Journal of Mammary Gland Biology & Neoplasia (2017), 22(1), 1-11

Estrogens are the subject of intensive researches aiming to elucidate their mechanism of action on the various tissues they target and especially on mammary gland and breast cancer. The use of ready-to ... [more ▼]

Estrogens are the subject of intensive researches aiming to elucidate their mechanism of action on the various tissues they target and especially on mammary gland and breast cancer. The use of ready-to-use slow releasing devices to administer steroids, especially estrogens, to small experimental animals remains the method of choice in terms of animal well-being and of safety for both the researcher and the animal. In this study, we evaluated and compared, in vitro and in vivo, the release kinetic of estradiol (E2) over sixty days from two different slow-releasing systems: the matrix pellet (MP) and the reservoir implant (RI). We compared the impact of these systems in three E2-sensitive mouse models : mammary gland development, human MCF7 adenocarcinoma xenograft and mouse melanoma progression. The real amount of E2 that is released from both types of devices could differ from manufacturer specifications due to inadequate release for MP and initial burst effect for RI. Compared to MP, the interindividual variability was reduced with RI thanks to a superior control of the E2 release. Depending on the dose-dependent sensitivity of the physiological or pathological readout studied, this could lead to an improvement of the statistical power of in vivo experiments and thus to a reduction of the required animal number. Altogether, our data draw attention on the importance to adequately select the slow-releasing device that is the most appropriated to a specific experiment to better fulfill the 3Rs rule (Replacement, Reduction, Refinement) related to animal welfare and protection. [less ▲]

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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 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 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 detailSepramesh and postoperative peritoneal adhesions in a rat model
Arung, Willy; Drion, Pierre ULg; DETRY, Olivier ULg

in Acta Chirurgica Belgica (2016), 116(6), 357-361

Purpose: The present study aimed to investigate the safety and the anti-postoperative peritoneal adhesion (PPA) characteristics of SeprameshVR (Davol), a composite mesh made of polypropylene covered with ... [more ▼]

Purpose: The present study aimed to investigate the safety and the anti-postoperative peritoneal adhesion (PPA) characteristics of SeprameshVR (Davol), a composite mesh made of polypropylene covered with Seprafilm, when intraperitoneally placed in a rat model. Methods: Twenty male rats were randomized into a control group and a Sepramesh group. They underwent a primary surgical procedure aiming to induce a peritoneal injury in order to induce PPAs. In the Sepramesh group, the burnt peritoneum was covered with a 2-cm diameter disc of Sepramesh prosthesis. The mesh was fixed to the parietal peritoneum with four 3-0 absorbable stitches. PPAs were assessed during a second laparotomy 10 days later using quantitative and qualitative scoring systems. Results: There was no difference in terms of mean number of PPAs between both groups. All the rats from the control group developed PPAs. In the Sepramesh group, no adhesions were observed at the site of the injured peritoneum that had been covered with the Sepramesh prosthesis, but PPAs occurred at the extremities of the mesh, where there was close contact between polypropylene and viscera, or where the fixation sutures were placed. The severity and the type of adhesions were significantly higher in the control group. Conclusions: This study demonstrated that for the Sepramesh prostheses, the Seprafilm layer might be effective in PPA prevention, but damage caused by the section and fixation of Sepramesh should be limited in order to limit PPAs. [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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See detailImpact of biomaterial microtopography on bone regeneration: comparison of three hydroxyapatites
LAMBERT, France ULg; Bacevic, Miljana ULg; Layrolle, Pierre et al

in Clinical Oral Implants Research (2016)

Aims: The primary objective of this study was to compare the in vivo performance, namely in terms of quantity of newly formed bone and bone-to-material contact (osteoconductivity), of three hydroxyapatite ... [more ▼]

Aims: The primary objective of this study was to compare the in vivo performance, namely in terms of quantity of newly formed bone and bone-to-material contact (osteoconductivity), of three hydroxyapatite-based biomaterials (HA) of different origins (natural or synthetic) or manufacturing process in a sinus lift model in rabbits. The secondary objective was to correlate the findings with the physical and topographical characteristics of the biomaterials. Materials and Methods: Two bovine HA manufactured with different processes (bovine hydroxyapatites [BHA] and cuttlebone hydroxyapatite [CBHA]) and a synthetic hydroxyapatite (SHA) sintered at high temperature were characterised with scanning electronic microscopy (SEM) and the measurement of specific surface area (BET). The materials were implanted in a sinus lift model in rabbits; histological and histomorphometric evaluation using non-decalcified sections was performed at 1, 5 and 12 weeks after implantation. Results: The studied biomaterials displayed a different surface topography. The two natural HA displayed significantly higher bone quantities (P = 0.0017; BHA vs. SHA, P = 0.0018 and CBHA vs. SHA, P = 0.033) at 5 and 12 weeks compared to the synthetic one (SHA). Moreover, the osteoconductivity (bone-to-material contact) was significantly higher in the BHA group compared to the two other groups (P = 0.014; BHA vs. SHA, P = 0.023 and BHA vs. CBHA, P = 0.033). Conclusion: HA-based biomaterials from diverse origins and manufacturing processes displayed different topographical characteristics. This may have influenced different regenerated bone architecture observed; more bone was found with natural HA compared to the synthetic one, and significantly higher bone-to-material contacts were found with BHA. [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

Poster (2016, October 14)

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 detail68Ga and 188Re Starch-Based Microparticles as Theranostic Tool for the Hepatocellular Carcinoma: Radiolabeling and Preliminary In Vivo Rat Studies
Verger, Elise ULg; Drion, Pierre ULg; MEFFRE, Geneviève ULg et al

in PLoS ONE (2016)

This work aims to develop, validate and optimize the radiolabeling of Starch-Based Microparticles (SBMP) by 188Re and 68Ga in the form of ready-to-use radiolabeling kits, the ultimate goal being to obtain ... [more ▼]

This work aims to develop, validate and optimize the radiolabeling of Starch-Based Microparticles (SBMP) by 188Re and 68Ga in the form of ready-to-use radiolabeling kits, the ultimate goal being to obtain a unique theranostic vector for the treatment of Hepatocellular Carcinoma. METHODS: Optimal labeling conditions and composition of freeze-dried kits were defined by monitoring the radiochemical purity while varying several parameters. In vitro stability studies were carried out, as well as an in vivo biodistribution as a preliminary approach with the intra-arterial injection of 68Ga radiolabeled SBMP into the hepatic artery of DENA-induced rats followed by PET/CT imaging. RESULTS: Kits were optimized for 188Re and 68Ga with high and stable radiochemical purity (>95% and >98% respectively). The in vivo preliminary study was successful with more than 95% of activity found in the liver and mostly in the tumorous part. CONCLUSION: SBMP are a promising theranostic agent for the Selective Internal Radiation Therapy of Hepatocellular carcinoma [less ▲]

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See detailAzacytidine mitigates experimental sclerodermic chronic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

in Journal of Hematology & Oncology (2016), 9

Background <br />Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express ... [more ▼]

Background <br />Previous studies have demonstrated that regulatory T cells (Tregs) play a protective role in the pathogenesis of chronic graft-versus-host disease (cGVHD). Tregs constitutively express the gene of the transcription factor Foxp3 whose CNS2 region is heavily methylated in conventional CD4+ T cells (CD4+Tconvs) but demethylated in Tregs. <br />Methods <br />Here, we assessed the impact of azacytidine (AZA) on cGVHD in a well-established murine model of sclerodermic cGVHD (B10.D2 (H-2d) → BALB/cJ (H-2d)). <br />Results <br />The administration of AZA every 48 h from day +10 to day +30 at the dose of 0.5 mg/kg or 2 mg/kg mitigated chronic GVHD. Further, AZA-treated mice exhibited higher blood and thymic Treg frequencies on day +35, as well as higher demethylation levels of the Foxp3 enhancer and the IL-2 promoter in splenocytes at day +52. Interestingly, Tregs from AZA-treated mice expressed more frequently the activation marker CD103 on day +52. AZA-treated mice had also lower counts of CD4+Tconvs and CD8+ T cells from day +21 to day +35 after transplantation, as well as a lower proportion of CD4+Tconvs expressing the Ki67 antigen on day +21 demonstrating an anti-proliferating effect of the drug on T cells. <br />Conclusions <br />Our results indicate that AZA prevented sclerodermic cGVHD in a well-established murine model of cGVHD. These data might serve as the basis for a pilot study of AZA administration for cGVHD prevention in patients at high risk for cGVHD. [less ▲]

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See detail188Re and 68Ga radiolabeled Starch-Based Microparticles as potential theranostic radiopharmaceutical for Hepatocellular Carcinoma
Verger, Elise ULg; Drion, Pierre ULg; MEFFRE, Geneviève ULg et al

in Journal of Nuclear Medicine (The) (2016, May 01), 57(suppl. 2),

The SBMP as a unique vector is a promising theranostic agent for the SIRT of HCC.

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See detailMicroparticules à base d’amidon radiomarquées au 188Re et 68Ga comme agent théranostique pour la radiothérapie interne sélective du carcinome hépatocellulaire
Verger, Elise ULg; Drion, Pierre ULg; MEFFRE, Geneviève ULg et al

in Médecine Nucléaire (2016, May), 40(3), 182

Les microparticules SBMP, en étant capable d'être radiomarquées rapidement, de manière reproductible, sous forme de kits prêt-à-l‘emploi, par du 188Re et du 68Ga, se révèlent être un outil théranostique ... [more ▼]

Les microparticules SBMP, en étant capable d'être radiomarquées rapidement, de manière reproductible, sous forme de kits prêt-à-l‘emploi, par du 188Re et du 68Ga, se révèlent être un outil théranostique prometteur pour le traitement du carcinome hépatocellulaire. [less ▲]

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See detailAzacytidine Enhances Regulatory T-Cells In Vivo and Prevents Experimental Xenogeneic Graft-Versus-Host Disease
Ehx, Grégory ULg; Fransolet, Gilles ULg; de Leval, Laurence ULg et al

in Biology of Blood and Marrow Transplantation (2016, March), 22(3), 393

Background. 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 ... [more ▼]

Background. 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 (Tregs). Objective. We investigated the impact of AZA on xenogeneic graft-versus-host disease (xGVHD) in a humanized murine model of transplantation, and described the impact of the drug on human T cells in vivo. Methods. In order to induce xGVHD, human peripheral blood mononuclear cells (huPBMC) were administered intravenously in NOD-scid IL-2Rγnull (NSG) mice. Results. AZA successfully improved both survival (p<0.0001) and xGVHD scores (p<0.0001). Further, AZA significantly decreased human T-cell proliferation as well as INF-γ and TNF-α serum levels, and reduced the expression of GRANZYME B and PERFORIN 1 by cytotoxic T cells. In addition, AZA administration significantly increased the function, proliferation and frequency of Tregs through demethylation of FOXP3i1 and higher secretion of IL-2 by conventional T cells due to IL2 gene promoter site 1 demethylation. Interestingly, among AZA-treated mice surviving the acute phase of xGVHD, there was an inverse correlation between the presence of Tregs and signs of chronic GVHD. Finally, Tregs harvested from the spleen of AZA-treated mice were suppressive and stable over time since they persisted at high frequency in secondary transplant experiments. Conclusion. These findings emphasize a potential role for AZA as prevention or treatment of GVHD and other autoimmune diseases. [less ▲]

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See detailImmunomodulatory effects of rapamycin in Graft versus Host Disease
Ehx, Grégory ULg; Hannon, Muriel ULg; Humblet-Baron, Stéphanie et al

Poster (2016, January 29)

Graft-versus-host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Several studies have shown 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 (HSCT). Several studies have shown that rapamycin (RAPA), an mTOR inhibitor with immunosuppressive properties, may reduce GVHD severity and mortality, notably by favoring regulatory T cells (Tregs) proliferation in vivo and in vitro. However, few data have been reported about the global impact of this drug on the immune system in the context of GVHD. The present work investigates the mechanisms by which RAPA impacts GVHD both in a xenogeneic GVHD mouse model (NSG mice transplanted with human PBMC) and in patients receiving postgrafting immunosuppression with tacro + RAPA versus patients receiving tacro + MMF. In mice, our results show that RAPA injections significantly reduces xenogeneic GVHD lethality and severity. Flow cytometric analyses highlighted a strong reduction of human cells chimerism in mice together with higher 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-). 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. In patients, preliminary results show that RAPA significantly reduce CD8+ T cells count in agreement with mouse experiments. 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 detailAzacytidine and Decitabine prevent experimental sclerodermic chronic graft-versus-host disease
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

Poster (2016, January 29)

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following allo-transplantation, 60% of the patients experience ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Following allo-transplantation, 60% of the patients experience chronic GVHD while approximately 15% of them develop a sclerodermic form of chronic GVHD characterized by multiple organ fibrosis and loss of skin elasticity. Regulatory T cells (Tregs) play a pivotal protective role in the pathogenesis of chronic GVHD by inhibiting alloreactive conventional T cells (Tconvs). Several studies have shown that hypomethylating agents such as Azacytidine (AZA) or Decitabine (DAC) can demethylate the master transcription factor of Treg (FoxP3), thus promoting Treg differentiation from Tconvs. This work investigates the impact of AZA and DAC in a murine model of sclerodermic chronic GVHD. Methods: Lethally irradiated (7 Gy) BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107splenocytes from B10.D2 donor mice to induce scl-cGVHD. Recipients were injected with 0.5 or 2 mg/kg of AZA or 0.75 mg/kg of DAC every 48h from day 10 to 30 following transplantation. GVHD was scored using a five criteria scale (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10. Results: Mice treated with AZA 0.5 mg/kg (n=14) or 2 mg/kg (n=17) or DAC 0.75 mg/kg (n=5) had lower clinical scores of GVHD compared to control (n=15). FACS analyses showed a higher proportion of Treg in the blood of AZA 0.5 or 2 mg/kg or DAC 0.75 mg/kg mice than in control at day 35. Results also showed a decreased number of Tconv and CD8 in AZA and DAC treated mice while proliferation of these cells expressing Ki67 was lower during AZA/DAC treatment but higher after discontinuation. Histological analyses showed less skin fibrosis in mice treated with 2 mg/kg of AZA. Finally, analyses of the blood components demonstrated that AZA mice were leuco- and lymphopenic as compared to control at day 21 and 35. Conclusion : AZA and DAC prevented sclerodermic GVHD in this murine model. [less ▲]

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Peer Reviewed
See detailMultimodality imaging assessment of the deleterious role of the intraluminal thrombus on the growth of abdominal aortic aneurysm in a rat model
NCHIMI LONGANG, Alain ULg; Courtois, Audrey ULg; EL HACHEMI, Mounia ULg et al

in European Radiology (2016), 26

Objectives To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. Methods The post-induction ... [more ▼]

Objectives To evaluate imaging changes occurring in a rat model of elastase-induced abdominal aortic aneurysm (AAA), with emphasis on the intraluminal thrombus (ILT) occurrence. Methods The post-induction growth of the AAA diameter was characterized using ultrasound in 22 rats. ILT was reported on 13 rats that underwent 14 magnetic resonance imaging (MRI) 2-18 days post-surgery, and on 10 rats that underwent 18 fluoro-deoxyglucose (FDG) positron emission tomography (PET)/microcomputed tomography examinations 2-27 days post-surgery. Logistic regressions were used to establish the evolution with time of AAA length, diameter, ILT thickness, volume, stratification, MRI and FDG PET signalling properties, and histological assessment of inflammatory infiltrates. Results All of the following significantly increased with time post-induction (p < 0.001): AAA length, AAA diameter, ILT maximal thickness, ILT volume, ILT iron content and related MRI signalling changes, quantitative uptake on FDG PET, and the magnitude of inflammatory infiltrates on histology. However, the aneurysm growth peak followed occurrence of ILT approximately 6 days after elastase infusion. Conclusion Our model emphasizes that occurrence of ILT precedes AAA peak growth. Aneurysm growth is associated with increasing levels of iron, signalling properties changes in both MRI and FDG PET, relating to its biological activities. [less ▲]

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See detailL'Azacytidine comme traitement de la maladie du greffon contre l'hôte de type chronique sclérodermique expérimentale.
Fransolet, Gilles ULg; Ehx, Grégory ULg; SOMJA, Joan ULg et al

Conference (2015, November 19)

Introduction: Graft-versus-host disease (GVHD) has remained a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) for the last decades. Following unmanipulated peripheral-blood ... [more ▼]

Introduction: Graft-versus-host disease (GVHD) has remained a major complication of allogeneic hematopoietic stem cell transplantation (HSCT) for the last decades. Following unmanipulated peripheral-blood stem cell transplantation, 60% of the patients experience chronic GVHD while approximately 15% of them develop a sclerodermic form of chronic GVHD characterized by multiple organ fibrosis and loss of skin elasticity. Regulatory T cells (Tregs) play a pivotal protective role in the pathogenesis of chronic GVHD by inhibiting alloreactive conventional T cells (Tconvs). Several studies have shown that hypomethylating agents such as azacytidine (Aza) can demethylate the master transcription factor of Treg (Forkhead box protein 3 factor, FoxP3), thus promoting Treg differentiation from Tconvs. This work investigates the impact of Aza in a classical murine model of sclerodermic chronic GVHD (B10.D2  BALB/cJ). Methods: In vitro analyses have been performed to determine the impact of Aza on collagen production. NIH-3T3 fibroblastic cells were plated and stimulated with 50 ng of PDGF or 10 ng of TGF-beta. Cells were then cultured with various concentrations of Aza for 48 hours. After culture, cells were stained with Sirius Red before quantification of collagen amount by absorbance at 490 nm. For in vivo experiments, lethally irradiated (7 Gy) BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107splenocytes from B10.D2 donor mice to induce scl-cGVHD. Recipients were injected with either 0,5 or 2 mg/kg of Aza every 48 hours from day 10 to 30 following transplantation. GVHD was scored using a five criteria scale (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10 (or > 20% weight loss) or at day 52 after transplantation (end of experiment). Results: Concerning in vitro analyses, results suggest a decreased production of collagen at higher concentration of Aza with both stimulations (seen by a gradual diminution of absorbance). For in vivo experiments, mice treated with Aza 0.5 mg/kg (n = 14) or 2 mg/kg (n = 25) had significant lower clinical scores of GVHD compared to control ones (n = 23) after treatment. FACS analysis showed a higher proportion of Treg among CD4+ T cells in the blood of Aza 2 mg/kg mice than in control mice at day 35 following transplantation (P = 0.047), as well as a higher percentage of Tregs expressing the KI67 proliferative marker on the same time point (P = 0.0005). Finally, analyses of the cellular blood components with Cell-dyn demonstrated that Aza 2 mg/kg treated mice were significantly lymphopenic as compared to control mice at day 35 after transplantation (P = 0.05). Conclusion : Aza prevented sclerodermic GVHD in this classical murine model of chronic GVHD. [less ▲]

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