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See detailEstablishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation
Binsfeld, Marilène ULg; Beguin, Yves ULg; Belle, Ludovic et al

in PLoS ONE (in press)

Background: Multiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic ... [more ▼]

Background: Multiple myeloma (MM) is a malignant plasma cell disorder with poor long-term survival and high recurrence rates. Despite evidence of graft-versus-myeloma (GvM) effects, the use of allogeneic hematopoietic stem cell transplantation (allo-SCT) has remained controversial in MM. In the current study, we investigated the anti-myeloma effects of allo-SCT from B10.D2 mice into MHC-matched myeloma-bearing Balb/cJ mice (previously injected with the MOPC315.BM myeloma cell line), based on a chronic graft-versus-host disease (GvHD) murine model. Methods and results: Balb/cJ mice were injected intravenously with luciferase-transfected MOPC315.BM cells, and received 30 days later an allogeneic (B10.D2 donor) or autologous (Balb/cJ donor) transplantation by intravenous administration of bone marrow cells and splenocytes. We observed a graft-versus-myeloma effect in 94% of the allogeneic transplanted mice, as luciferase signal completely disappeared after transplantation, whereas all the autologous transplanted mice showed myeloma evolution. Lower serum paraprotein levels and myeloma infiltration in bone marrow and spleen in the allogeneic setting confirmed the observed GvM effect, while allogeneic mice also displayed chronic GvHD symptoms. In vivo and in vitro data suggest the involvement of effector memory CD4 and CD8 T cells in the GvM effect. The essential role of CD8 T cells was demonstrated in vivo where CD8 T-cell depletion of the graft resulted in reduced GvM effects. Finally, TCR V spectratyping analysis identified V families within CD4 and CD8 T cells which were associated with both GvM effects and GVHD, whereas other V families within CD4 T cells were associated exclusively with either GvM or GvHD responses. Conclusions: We successfully established an immunocompetent murine model of graft-versus-myeloma. This is the first immunocompetent murine model which is based on a MM model closely resembling human MM disease (bone marrow tropism, ...) and using allo-SCT after the disease establishment, as a curative treatment [less ▲]

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See detailInfusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease
Hannon, Muriel ULg; LECHANTEUR, Chantal ULg; Lucas, Sophie et al

in Transfusion (2014), 54(February), 353-363

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See detailImmunomodulatory effects of Rapamycin in xenogeneic GVHD
Ehx, Grégory ULg; HANNON, Muriel ULg; DUBOIS, Sophie ULg et al

Poster (2014, January 27)

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See detailThinking out of the box - New approaches to controlling GVHD
Baron, Frédéric ULg; Humblet-Baron, Stéphanie; Ehx, Grégory ULg et al

in Current Hematologic Malignancy Reports (2014), 9

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD ... [more ▼]

Graft-versus-host disease (GVHD) remains a major limitation of allogeneic hematopoietic cell transplantation (allo-HCT). Despite major advances in the understanding of GVHD pathogenesis, standard GVHD prophylaxis regimens continue to bebased on the combination of a calcineurin inhibitor with an antimetabolite, while first line treatmentsstill relies on high-dose corticosteroids. Further, no second line treatment has emerged thus far in acute or chronic GVHD patients who failed on corticosteroids. After briefly reviewing current standards of GVHD prevention and treatment, this article will discuss recent approaches that might change GVHD prophylaxis / treatment in the next decades, with a special focus on recently developed immunoregulatory strategies based on infusion of mesenchymal stromal or regulatory T-cells, or on injection of lowdose interleukin-2. [less ▲]

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See detailEstablishment of a murine graft-versus-myeloma model using allogeneic stem cell transplantation.
Binsfeld, Marilène ULg; BEGUIN, Yves ULg; Belle, Ludovic et al

in Belgian Journal of Hematology (2014)

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See detailImpact of bone marrow-derived mesenchymal stromal cells on experimental xenogeneic graft-versus-host disease
Bruck, France; Belle, Ludovic ULg; LECHANTEUR, Chantal ULg et al

in Cytotherapy (2013), 15(3), 267-279

Background aims. Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous ... [more ▼]

Background aims. Graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation caused by donor T cells reacting against host tissues. Previous studies have suggested that mesenchymal stromal cells (MSCs) could exert potent immunosuppressive effects. Methods. The ability of human bone marrow derived MSCs to prevent xenogeneic GVHD in non-obese diabetic/severe combined immunodeficient (NOD/SCID) mice and in NOD/SCID/interleukin-2Rg(null) (NSG) mice transplanted with human peripheral blood mononuclear cells (PBMCs) was assessed. Results. Injection of 200 106 human PBMCs intraperitoneally (IP) into sub-lethally (3.0 Gy) irradiated NOD/SCID mice also given anti-asialo GM1 antibodies IP 1 day prior and 8 days after transplantation induced lethal xenogeneic GVHD in all tested mice. Co-injection of 2 106 MSCs IP on day 0 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Similarly, injection of 30 106 human PBMCs IP into sub-lethally (2.5 Gy) irradiated NSG mice induced a lethal xenogeneic GVHD in all tested mice. Injection of 3 106 MSCs IP on days 0, 7, 14 and 21 did not prevent lethal xenogeneic GVHD induced by injection of human PBMCs. Conclusions. Injection of MSCs did not prevent xenogeneic GVHD in these two humanized mice models. [less ▲]

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See detailComparison of Immune Reconstitution after Hematopoietic Stem Cell Transplantation with Flu-TBI versus TLI-ATG Conditioning
Hannon, Muriel ULg; Humblet-Baron, S.; Graux, C. et al

in Belgian Journal of Hematology (2013), Abstracts book(Supplement of 28th General Meeting of the Belgian Hematological Society), 38

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See detailInfusion of CliniMACS (Myltenyi Biotec) Enriched Regulatory T Cells Delays Experimental Xenogeneic Graft-versus-Host Disease
Hannon, Muriel ULg; Lechanteur, C.; Somja, Joan ULg et al

in Belgian Journal of Hematology (2013), Abstracts book(Supplement of 28th General Meeting of the Belgian Hematological Society), 15

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See detailThe Immunomodulating Peptide Thymosin Alpha 1 Has no Effect on Multiple Myeloma Evolution and on Immune Reconstitution
Binsfeld, Marilène ULg; Otjacques, Eléonore ULg; Hannon, Muriel ULg et al

in Belgian Journal of Hematology (2013), Abstracts book(Supplement of 28th General Meeting of the Belgian Hematological Society), 41

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See detailKinetics of IL-7 and IL-15 Levels after Allogeneic Peripheral Blood Stem Cell Transplantation following Nonmyeloablative Conditioning
De Bock, Muriel; Fillet, Marianne ULg; Hannon, Muriel ULg et al

in PLoS ONE (2013), 8(2), 55876

Background: We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning. Methods: EDTA-anticoagulated plasma and serum samples were ... [more ▼]

Background: We analysed kinetics of IL-7 and IL-15 levels in 70 patients given peripheral blood stem cells after nonmyeloablative conditioning. Methods: EDTA-anticoagulated plasma and serum samples were obtained before conditioning and about once per week after transplantation until day 100. Samples were aliquoted and stored at 280uC within 3 hours after collection until measurement of cytokines. IL-7 and IL-15 levels were measured by ELISAs. Results: Median IL-7 plasma levels remained below 6 pg/L throughout the first 100 days, although IL-7 plasma levels were significantly higher on days 7 (5.1 pg/mL, P = 0.002), 14 (5.2 pg/mL, P,0.001), and 28 (5.1 pg/mL, P = 0.03) (but not thereafter) than before transplantation (median value of 3.8 pg/mL). Median IL-15 serum levels were significantly higher on days 7 (12.5 pg/mL, P,0.001), 14 (10.5 pg/mL, P,0.001), and 28 (6.2 pg/mL, P,0.001) than before transplantation (median value of 2.4 pg/mL). Importantly, IL-7 and IL-15 levels on days 7 or 14 after transplantation did not predict grade II–IV acute GVHD. Conclusions: These data suggest that IL-7 and IL-15 levels remain relatively low after nonmyeloablative transplantation, and that IL-7 and IL-15 levels early after nonmyeloablative transplantation do not predict for acute GVHD. [less ▲]

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See detailRapamycin Prevents Experimental Sclerodermatous Chronic Graft-versus-Host Disease in mice
Belle, Ludovic ULg; Binsfeld, Marilène ULg; DUBOIS, Sophie ULg et al

in Belgian Journal of Hematology (2012), Abstracts book(Supplement of 27th General Meeting of the Belgian Hematological Society), 14

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See detailWhat is the Contribution of Host-Derived CMV Immunity after Allogeneic Transplantation following Non-Myeloablative Conditioning?
MENTEN, Catherine ULg; Castermans, E.; Hannon, Muriel ULg et al

in Haematologica (2012), 97(Supplement 1), 720

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See detailEvidence for Expansion of Host-derived CMV-specific CD8+ T cells after Allogeneic Transplantation with Non-Myeloablative Conditioning
MENTEN, Catherine ULg; Castermans, E.; Hannon, Muriel ULg et al

in Belgian Journal of Hematology (2012), Abstracts book(Supplement of 27th General Meeting of the Belgian Hematological Society), 16

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See detailRapamycin prevents experimental sclerodermatous chronic graft-versus-host disease in mice
Belle, Ludovic ULg; Binsfeld, Marilène ULg; DUBOIS, Sophie ULg et al

Conference (2012)

Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that ... [more ▼]

Background: The most widely used mice model of chronic graft-versus-host disease (cGvHD) is an MHC-matched bone marrow transplantation model of sclerodermatous cGvHD. A limitation of that model is that mortality is relatively low, making difficult to study the impact of potentially therapeutic compounds. Aims: To develop a more severe model of cGVHD and to assess the impact of Rapamycin administration in that model. Results: Lethally irradiated Balb/C mice were injected with 10x106 bone marrow cells and 70x106 splenocytes from B10.D2 donor mice. Twenty-one days later, all mice developed cGvHD. For the severe model, donor B10.D2 mice were injected with 0.5x106 splenocytes from Balb/C twenty-one days before transplantation. All mice from the severe model (n=8) died a median of 32 days while 3 of 7 mice in the classical model survived beyond day 52. Mean survival was decreased in the severe model compared to the classical model (32 days versus 37 days; p=0.0185). Recipient mice in the severe group experienced higher weight loss, hair loss and skin fi brosis. Numbers of T lymphocytes (231.9 ± 151.4 versus 951 ± 532.8; p=0.0032) and CD4+ T cells (63.25 ± 41.93 versus 135.0 ± 14.39; p=0.0018) per microliter of blood at day 21 were lower in the severe group than in the classical model. Moreover, number of regulatory T cells (Tregs) was decreased in the severe model (1.250 ± 0.8864 versus 8.000 ± 6.753; p=0.0151). We then investigated whether rapamycin administration could prevent GVHD in the severe model. All (n=8) mice treated with PBS (placebo) died a median of 32 days after transplantation, while 6 of 8 mice given 1 mg/kg/day i.p. rapamycin survived beyond day 52 (p=0.0012). Number of Tregs/μl was higher at day 21 in rapamycin-treated mice than in mice given PBS (2.000±1.195 versus 1.250±0.8864; p=0.0796). Moreover, number of naïve CD4+T (10.00±4.192 versus 30.25±5.185; p= 0.0089) and effector memory T cells (EMT) (30.67±3.180 versus 67.33±7.881; p= 0.0125) were higher in rapamycin mice. Finally, proliferation of EMT (assessed by fl ow cytometry using Ki-67) was higher in PBS than in rapamycin mice (45.28%±4.084 versus 31.90%± 2.003; p=0.0474). Conclusion: We have developed a mice model of severe cGVHD. Interestingly, rapamycin prevented death from cGVHD in that model, perhaps through in vivo expansion of Treg. [less ▲]

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See detailBone marrow-derived mesenchymal stromal cells failed to prevent experimental xenogeneic graft-versus-host disease
Bruck, France; de Leval, Laurence; Belle, Ludovic ULg et al

Poster (2012)

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