[en] Introduction: Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation (HSCT). Approximately 15% of the patients develop the sclerodermatous cGvHD (scl-cGvHD) form of the disease characterized by multiple organ fibrosis and loss of skin elasticity. A few studies have suggested potential benefits of imatinib, a tyrosine kinase inhibitor, as a treatment of fibrosis in scl-cGVHD due to its ability to inhibit simultaneously the PDGF receptor and TGF-β pathways (via ABL inhibition), which are both involved in fibrosis .
Aim: This work investigates the impact of imatinib on fibrosis in the B10.D2 to BALB/cJ scl-cGvHD murine model. Lethally irradiated BALB/cJ recipient mice were injected with 107 bone marrow cells + 7.107 splenocytes from B10.D2 donor mice. Recipients were treated with imatinib 150 mg/kg/day (50 mg/kg in the morning followed by 100 mg/kg in the evening) by oral gavage or the same volume of sterile water. Mice health status was evaluated with a scoring system encompassing five criteria (weight loss, activity, fibrosis, hair loss and mice posture; 0-1-2 points/criteria). Mice were sacrificed at a score of 8/10 according to our local ethical committee.
Results: Mice given daily 150 mg/kg imatinib had a better survival than control mice (42 versus 33 days, p = 0,0357). cGvhD scores were suggestively lower in imatinib-treated than in control mice (p ≤ 0,15). Further, histological analyses evidenced reduction in the levels of both PDGF receptor (p = 0,033) and c-Abl (p = 0,185) phosphorylation in imatinib as compared to control mice. Finally, no significant differences were observed in the number or frequency of lymphocyte subsets in the 2 groups of mice.
Conclusion: Imatinib slightly decreased fibrosis and significantly improved survival in a severe scl-cGvHD murine model.
Research center :
GIGA-I3 - Giga-Infection, Immunity and Inflammation - ULiège
Imatinib improves survival of chronic Graft-versus-host disease by inhibiting TGF-β and PDGF-R in mice
Alternative titles :
[fr] L'imatinib améliore la survie de la maladie du greffon contre l'hôte de type chronique par inhibition du TGF-β et du PDGFR chez la souris
Publication date :
January 2014
Number of pages :
A0
Event name :
29th general annual meeting of the Belgian Hematological Society
Event organizer :
Belgian Hematological Society
Event place :
Ghent, Belgium
Event date :
Du 28 janvier 2014 au 30 janvier 2014
Name of the research project :
Effets in vitro et in vivo de l'imatinib et du nilotinib, deux inhibiteurs de tyrosine kinase, dans la maladie du greffon contre l'hôte de type chronique sclérodermique
Funders :
F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE] Fonds Léon Fredericq [BE]