Limited Impact of Imatinib in a Murine Model of Sclerodermatous Chronic Graft-versus-Host Disease

Abstract

BackgroundSclerodermatous 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.MethodsTo 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).ResultsImatinib 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).ConclusionsImatinib had a limited impact in murine scl-cGVHD despite significant inhibition of PDGF-r.

New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions

“…used a murine model of Scl-cGvHD to assess the therapeutic impact of imatinib; published data indicated that imatinib is able to reduce the proliferation of both total T cells and T-regs in the spleen. Nevertheless, despite the inhibition of PDGFR, there was no significant clinical impact of imatinib on murine Scl-cGvHD ( 77 ). The impact of imatinib on liver fibrosis is more debated: indeed, it significantly decreased the expression of some fibrosis markers, such as α-SMA, Pcol1A1, and Hsp47 ( 94 ), but reduced only the early liver fibrogenesis without preventing the long-term fibrosis progression ( 95 ).…”

Kinase Inhibition as Treatment for Acute and Chronic Graft-Versus-Host Disease

“…applied imatinib in a murine model of Scl-cGvHD but found limited impact besides reduced PDGFR phosphorylation. T-cell proliferation was slightly inhibited, but GvHD scores were unchanged ( 141 ). Contrary to these findings, another study reported that both, imatinib and nilotinib prevent the development of Scl-GvHD in mice ( 142 ).…”