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

Abstract

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.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 sclérodermiqu