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See detailInfusion of mesenchymal stromal cells after deceased liver transplantation: A phase I-II, open-label, clinical study.
DETRY, Olivier ULg; VANDERMEULEN, Morgan ULg; DELBOUILLE, Marie-Hélène ULg et al

in Journal of Hepatology (2017), 67(1), 47-55

BACKGROUND & AIM: Mesenchymal stromal cell (MSC) infusion could be a mean to establish tolerance in solid organ recipients. The aim of this prospective, controlled, phase-1 study was to evaluate the ... [more ▼]

BACKGROUND & AIM: Mesenchymal stromal cell (MSC) infusion could be a mean to establish tolerance in solid organ recipients. The aim of this prospective, controlled, phase-1 study was to evaluate the feasibility, safety and tolerability of a single infusion of MSCs in liver transplant recipients. METHODS: Ten liver transplant recipients under standard immunosuppression received 1.5-3x106/kg third-party unrelated MSCs on post-operative day 3+/-2, and were prospectively compared to a control group of 10 liver transplant recipients. As primary end-points, MSC infusional toxicity was evaluated, and infectious and cancerous complications were prospectively recorded until month 12 in both groups. As secondary end-points, rejection rate, month-6 graft biopsies, and peripheral blood lymphocyte phenotyping were compared. Progressive immunosuppression weaning was attempted from month 6 to 12 in MSC recipients. RESULTS: No variation in vital parameters or cytokine release syndrome could be detected during and after MSC infusion. No patient developed impairment of organ functions (including liver graft function) following MSC infusion. No increased rate of opportunistic infection or de novo cancer was detected. As secondary end-points, there was no difference in overall rates of rejection or graft survival. Month-6 biopsies did not demonstrate a difference between groups in the evaluation of rejection according to the Banff criteria, in the fibrosis score or in immunohistochemistry (including Tregs). No difference in peripheral blood lymphocyte typing could be detected. The immunosuppression weaning in MSC recipients was not successful. CONCLUSIONS: No side effect of MSC infusion at day 3 after liver transplant could be detected, but this infusion did not promote tolerance. This study opens the way for further MSC or Treg-based trials in liver transplant recipients. LAY SUMMARY: Therapy with mesenchymal stromal cells (MSCs) has been proposed as a mean to improve results of solid organ transplantation. One of the potential MSC role could be to induce tolerance after liver transplantation, i.e. allowing the cessation of several medications with severe side effects. This study is the first-in-man use of MSC therapy in 10 liver transplant recipients. This study did not show toxicity after a single MSC infusion but it was not sufficient to allow withdrawal of immunosuppression. [less ▲]

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See detailOLFM4, KNG1 and Sec24C identified by proteomics and immunohistochemistry as potential markers of early colorectal cancer stages
QUESADA-CALVO, Florence ULg; MASSOT, Charlotte ULg; Bertrand, Virginie ULg et al

in Clinical Proteomics (2017), 24(9),

Abstract Background: Despite recent advances in colorectal cancer (CRC) diagnosis and population screening programs, the identification of patients with preneoplastic lesions or with early CRC stages ... [more ▼]

Abstract Background: Despite recent advances in colorectal cancer (CRC) diagnosis and population screening programs, the identification of patients with preneoplastic lesions or with early CRC stages remains challenging and is important for reducing CRC incidence and increasing patient’s survival. Methods: We analysed 76 colorectal tissue samples originated from early CRC stages, normal or inflamed mucosa by label-free proteomics. The characterisation of three selected biomarker candidates was performed by immunohisto‑ chemistry on an independent set of precancerous and cancerous lesions harbouring increasing CRC stages. Results: Out of 5258 proteins identified, we obtained 561 proteins with a significant differential distribution among groups of patients and controls. KNG1, OLFM4 and Sec24C distributions were validated in tissues and showed differ‑ ent expression levels especially in the two early CRC stages compared to normal and preneoplastic tissues. Conclusion: We highlighted three proteins that require further investigations to better characterise their role in early CRC carcinogenesis and their potential as early CRC markers. [less ▲]

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See detailProteomic differential distribution of 53BP1 in serrated and conventional adenomas validated by histological characterisation
QUESADA-CALVO, Florence ULg; Merli, Angela-Maria ULg; MASSOT, Charlotte ULg et al

Poster (2017, February 10)

INTRODUCTION: Sessile serrated adenoma/polyp (SSA/p) is a precancerous lesion, mostly located in the right side of the colon (cecum, ascending and transverse colon). The difficulty is to visualize this ... [more ▼]

INTRODUCTION: Sessile serrated adenoma/polyp (SSA/p) is a precancerous lesion, mostly located in the right side of the colon (cecum, ascending and transverse colon). The difficulty is to visualize this lesion during colonoscopy because of its subtle appearance. MATERIAL AND METHOD: We compared proteomes of serrated polyps (SSA/p) and conventional adenomas using residual human formalin fixed paraffin embedded (FFPE) samples. FFPE-FASP method was applied on samples before label free proteomic analysis. Immunohistochemistry (IHC) characterisation of one candidate marker was performed for tissue validation on an independent set of samples including: conventional adenomas (low and high-grade dysplasia), serrated polyps (hyperplastic polyps, SSA/p and traditional serrated adenoma) and finally normal colon (taken at the margin of colorectal cancer (CRC) or of diverticular disease). RESULTS: Proteomics provided 765 proteins (out of 5992 proteins identified) significantly discriminating conventional adenomas from serrated lesions. We selected 53BP1 (Tumor suppressor p53-binding protein 1) among these for IHC validation, because of its tumor suppressor gene function and role as a mediator of DNA damage checkpoint. 53BP1 appeared significantly up-regulated in proteomes of low and high grade adenomas compared to these of normal tissue and SSA/p. 53BP1 IHC signal was located in the nucleus and the percentage of positive nucleus decreased in serrated polyps, especially in crypts and in the border epithelium, confirming part of the proteomic results. CONCLUSION: This study highlights potential marker proteins, including 53BP1 from which IHC signal was strongly decreased in some serrated polyps. The loss of 53BP1 has been associated with tumour progression and poor prognosis, while little is currently known about its involvement in precancerous CRC lesions. 53BP1 decrease of expression in the nucleus and therefore possible loss of function in some epithelial cells could reflect important changes occurring during dysplasia to neoplasia progression in serrated lesions. [less ▲]

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See detailUNE INJECTION UNIQUE DE CELLULES STROMALES MESENCHYMATEUSES AU JOUR 3 APRES GREFFE HEPATIQUE EST INSUFFISANTE POUR INDUIRE UNE TOLERANCE OPERATIONNELLE
DETRY, Olivier ULg; VANDERMEULEN, Morgan ULg; DELBOUILLE, Marie-Hélène ULg et al

in Transplant International (2017, January), 30(suppl 1), 812

Introduction: Mesenchymal stromal cell (MSC) infusion could be a mean to establish donor-specific immunological tolerance in solid organ recipients. The aim of this phase 2 study was test the hypothesis ... [more ▼]

Introduction: Mesenchymal stromal cell (MSC) infusion could be a mean to establish donor-specific immunological tolerance in solid organ recipients. The aim of this phase 2 study was test the hypothesis of possible induction of operative tolerance by third-party MSC in liver transplant (LT) recipients. Methods: 10 stable and low-risk LT recipients under standard immunosup- pression (Tac-MMF- low dose steroids) received 1.5–3 9 106/kg third-party MSCs on post-operative day 3 ` 2. By protocol, progressive weaning of immunosuppression was attempted in patients who did not develop rejection and had normal graft function and month-6 graft biopsy. Tacrolimus was progressively tapered from day 180 to be discontinued by day 270. After day- 270 graft biopsy, MMF was progressively tapered and definitely discontinued by day 365 in the absence of rejection. Results: One patient from the MSC group was excluded from immunosup- pression withdrawal attempt due to HCC recurrence, and the 9 others met the necessary criteria. In one patient, tacrolimus and MMF withdrawal was performed without rejection. In two patients, MMF monotherapy was achieved at month 9, but graft rejection occurred during MMF withdrawal and was successfully treated by tacrolimus reintroduction. In 6 patients, the transam- inases significantly increased during tacrolimus withdrawal. In these cases, withdrawal was cancelled and liver tests normalised after increase of the tacrolimus dose. No graft was lost due to the withdrawal attempt. Conclusion: A single post transplant MSC injection is not sufficient to induce operative tolerance after LT. [less ▲]

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See detailMT4-MMP and EGFR expression levels are key biomarkers for breast cancer patient response to chemotherapy and erlotinib.
Yip, Cassandre ULg; Foidart, Pierre ULg; Somja, Joan ULg et al

in British Journal of Cancer (2017)

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a ... [more ▼]

BACKGROUND: Triple-negative breast cancers (TNBC) are heterogeneous cancers with poor prognosis. We aimed to determine the clinical relevance of membrane type-4 matrix metalloproteinase (MT4-MMP), a membrane type matrix metalloproteinase that interacts with epidermal growth factor receptor (EGFR) overexpressed in >50% of TNBC. METHODS: We conducted a retrospective immunohistochemical analysis on human TNBC samples (n=81) and validated our findings in in vitro and in vivo assays. RESULTS: Membrane type-4 matrix metalloproteinase and EGFR are produced in 72.5% of TNBC samples, whereas those proteins are faintly produced by healthy tissues. Unexpectedly, tumour relapse after chemotherapy was reduced in samples highly positive for MT4-MMP. Mechanistically, this is ascribed to a higher sensitivity of MT4-MMP-producing cells to alkylating or intercalating chemotherapeutic agents, as assessed in vitro. In sharp contrast, MT4-MMP expression did not affect tumour cell sensitivity to paclitaxel that interferes with protease trafficking. Importantly, MT4-MMP expression sensitised cancer cells to erlotinib, a tyrosine kinase EGFR inhibitor. In a pre-clinical model, the growth of MT4-MMP overexpressing xenografts, but not of control ones, was reduced by epirubicin or erlotinib. The combination of suboptimal drug doses blocked drastically the growth of MT4-MMP-producing tumours. CONCLUSIONS: We demonstrate that MT4-MMP defines a sub-population of TNBC sensitive to a combination of DNA-targeting chemotherapeutic agents and anti-EGFR drugs.British Journal of Cancer advance online publication 14 February 2017; doi:10.1038/bjc.2017.23 www.bjcancer.com. [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 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 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 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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See detailMT4-MMP, a potential prognostic factor in triple negative breast cancer
Yip, Cassandre ULg; FOIDART, Pierre ULg; SOMJA, Joan ULg et al

Scientific conference (2015, December 03)

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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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See detailInfusion of third-party mesenchymal stream cells after liver transplantation: a phase-1, open-label, clinical study
DETRY, Olivier ULg; VANDERMEULEN, Morgan ULg; DELBOUILLE, Marie-Hélène ULg et al

in Transplant International (2015, November), 28(S4), 1027

Background: Mesenchymal stromal cells (MSC) are multipotent bone mar- row progenitors that have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aimed ... [more ▼]

Background: Mesenchymal stromal cells (MSC) are multipotent bone mar- row progenitors that have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aimed to be the first evaluation of the safety and tolerability of MSC infusion after liver transplantation in a prospective, controlled phase-1 study. Methods: 10 liver transplant recipients under standard immunosuppression (TAC-MMF-low dose steroids until day 30) received 1.5–3 9 106/kg third party MSC on post-operative day 3 ` 2. These patients were prospectively compared to a group of 10 control liver recipients. Primary endpoints were MSC infusion toxicity, and incidence of cancer and opportunistic infections at month 6. Secondary endpoints were patient and graft survivals and rejection at month 6, as well as the effects of MSC on recipients’ immune function and on immunohistology of at month 6 graft biopsies. Results: No MSC infusional toxicity was observed. Both groups were comparable in terms of donor and recipient characteristics. There was no difference in primary end-points between control and MSC groups. No patient developed de novo cancer. There was no statistical difference in patient and graft survivals or in rejection rates. There was no graft rejection in the MSC group. Month-6 graft biopsies were not different according to Banff and fibrosis scores. Discussion: This phase 1 study showed excellent tolerability and safety of a single infusion of third-party MSC after liver transplantation. There were no graft safety issues and no excess of immunosuppression after MSC injection. Further analyses of consequences of MSC injection on the immune profile are needed. The possibility of avoiding calcineurin-inhibitors with repeated MSC injections as main immunosuppressive therapy and/of tolerance induction by MSC infusion should be investigated by further studies. This study is in part supported by an ESOT Senior Clinical Research Grant and by the University of Liege. [less ▲]

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See detailMT4-MMP, a potential therapeutic target in triple negative breast cancer
Yip, Cassandre ULg; FOIDART, Pierre ULg; SOMJA, Joan ULg et al

Poster (2015, September)

MT4-MMP and EGFR axis may have a significant role in patient outcome and response to EGFR targeted therapy. This axis is clinically relevant in TNBC, the most aggressive breast cancer subtype. TNBC are ... [more ▼]

MT4-MMP and EGFR axis may have a significant role in patient outcome and response to EGFR targeted therapy. This axis is clinically relevant in TNBC, the most aggressive breast cancer subtype. TNBC are known to express high level of EGFR and treatment options are limited due to the non response of to the EGFR targeted therapy. Expression levels of MT4-MMP and EGFR in TNBC may be used as prognosis factor for the selection of patient who may respond or not to EGFR targeted therapy. Also, our data shed light and the potential therapeutic option of targeting both MT4-MMP and EGFR in TNBC. [less ▲]

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See detailInfusion of third-party mesenchymal stromal cells after liver transplantation: a phase 1, open-label, clinical study
DETRY, Olivier ULg; VANDERMEULEN, Morgan ULg; DELBOUILLE, Marie-Hélène ULg et al

Poster (2015, March 27)

Transplanted patients have to deal with numerous side effects of life-long dependence on immunosuppressive drugs. Paradoxically these drugs fail to prevent acute and/or chronic rejection in many cases ... [more ▼]

Transplanted patients have to deal with numerous side effects of life-long dependence on immunosuppressive drugs. Paradoxically these drugs fail to prevent acute and/or chronic rejection in many cases. Mesenchymal stromal cells (MSC) are multipotent and self-renewing bone marrow progenitors that have been shown both in vitro and in vivo as capable of (i) immunomodulation, (ii) anti-inflammation in case of ischemia/reperfusion injury, and (ii) stimulation of tissue repair. MSC could therefore be very interesting in organ recipients to limit chronic graft damage and to allow tolerance. This study aimed to be the first clinical evaluation of the safety and tolerability of MSC infusion after liver transplantation in a prospective, controlled, phase I study. Clinical grade MSCs were locally collected from the bone marrow of unrelated healthy donors. They were cultured in a GMP-compliant lab, underwent extensive quality controls and were frozen for storage in a MSC bank. When needed for patient treatment, MSC were thawed and intravenously injected into patients. 10 liver transplant recipients under standard immunosuppression (TAC-MMF-low dose steroids until day 30) received 1.5-3x106/kg MSC on post- operative day 3 ± 2. These patients were prospectively compared to a group of 10 control (MSC-) liver recipients. Primary endpoints were MSC infusion toxicity, and incidence of cancer and opportunistic infections at month 6. Secondary endpoints were patient and graft survivals and rejection at month 6, as well as the effects of MSC on recipients’ immune function and on immunohistology of at month 6 graft biopsies. No MSC infusional toxicity was observed. Both groups were comparable in terms of donor and recipient characteristics. There was no difference in primary end-points between control and MSC groups. No patient developed de novo cancer. There was no statistical difference in patient and graft survivals or in rejection rates. There was no graft rejection in the MSC group. Month-6 graft biopsies were not different according to Banff and fibrosis scores. This phase I study showed excellent tolerability and safety of a single infusion of third-party MSC after liver transplantation. There were no graft safety issues and no excess of immunosuppression after MSC injection. Further analyses of consequences of MSC injection on the immune profile are needed. The possibility of avoiding calcineurin-inhibitors with repeated MSC injections as main immunosuppressive therapy and/of tolerance induction by MSC infusion should be investigated by further studies. [less ▲]

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