Belle Ludovic, Fransolet Gilles, Somja Joan, Binsfeld Marilène, Delvenne Philippe, Drion Pierre, Hannon Muriel, Beguin Yves, Ehx Grégory, Baron Frédéric
Hematology Research Unit, GIGA-I³, University of Liège, Liège, Belgium.
Department of Pathology, University of Liège, Liège, Belgium.
PLoS One. 2016 Dec 12;11(12):e0167997. doi: 10.1371/journal.pone.0167997. eCollection 2016.
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.
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).
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).
Imatinib had a limited impact in murine scl-cGVHD despite significant inhibition of PDGF-r.
硬皮病样慢性移植物抗宿主病（scl - cGVHD）是慢性移植物抗宿主病最严重的形式之一。血小板衍生生长因子（PDGF）和转化生长因子-β（TGF -β）在scl - cGVHD发生的纤维化过程中起重要作用。这促使我们评估PDGF - r和c - Abl酪氨酸激酶抑制剂伊马替尼对scl - cGVHD的影响。
为评估伊马替尼对体内T细胞亚群增殖的影响，对Balb/cJ受体小鼠进行7 Gy致死剂量照射，然后在第0天注射来自B10.D2小鼠的10×10⁶个骨髓细胞。14天后，注入70×10⁶个用羧基荧光素琥珀酰亚胺酯（CFSE）标记的来自B10.D2小鼠的脾细胞，并给予伊马替尼或无菌水5天。为诱导严重的scl - cGVHD，对Balb/cJ小鼠进行7 Gy照射后，静脉注射来自B10.D2供体小鼠的10.10⁶个骨髓细胞和70.10⁶个脾细胞。然后在移植后第7天至实验结束（第52天）给小鼠给予无菌水或伊马替尼。
伊马替尼降低了脾脏中总T细胞（P = 0.02）、CD8⁺T细胞（P = 0.01）和调节性T细胞（Tregs）（P = 0.02）的增殖。在严重的scl - cGVHD模型中，移植后第29天，伊马替尼治疗的小鼠PDGF - r磷酸化水平显著低于对照小鼠（P = 0.008）。然而，在整个实验过程中，载体治疗组和伊马替尼治疗组小鼠的scl - cGVHD评分相似，而伊马替尼治疗的小鼠体重减轻较少，在移植后第52天达到统计学显著性（P = 0.02）。
尽管伊马替尼对PDGF - r有显著抑制作用，但对小鼠scl - cGVHD的影响有限。
