title: Limited Impact of Imatinib in a Murine Model of Sclerodermatous Chronic Graft-versus-Host Disease.
abstract: 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).
  
  
  CONCLUSIONS
  Imatinib had a limited impact in murine scl-cGVHD despite significant inhibition of PDGF-r.
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Belle
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.
authors.forename: Gilles
authors.initials: G
authors.lastname: Fransolet
authors.affiliation: Department of Pathology, University of Liège, Liège, Belgium.
authors.forename: Joan
authors.initials: J
authors.lastname: Somja
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.
authors.forename: Marilène
authors.initials: M
authors.lastname: Binsfeld
authors.affiliation: Department of Pathology, University of Liège, Liège, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Delvenne
authors.affiliation: GIGA-R, University of Liège, Liège, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Drion
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.
authors.forename: Muriel
authors.initials: M
authors.lastname: Hannon
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.|Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Beguin
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.
authors.forename: Grégory
authors.initials: G
authors.lastname: Ehx
authors.affiliation: Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.|Department of Medicine, Division of Hematology, CHU of Liège, Liège, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000068877:Imatinib Mesylate / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D010982:Platelet-Derived Growth Factor / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D012594:Scleroderma, Localized / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
chemical_list: D010982:Platelet-Derived Growth Factor; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl