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首页> 外文期刊>Journal of Translational Medicine >Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment
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Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

机译：亚妥替尼恢复乳蛋白抗TNF剂量的组合优于标准抗TNF治疗临床和分子有动力学谱

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New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.
机译：在过去的几十年中出现了用于类风湿性关节炎（RA）的新药物，包括疾病改性抗抗肠药物（DMARDS）和生物学。然而，没有已知治愈，因为患者的大量比例留下或成为当前疗法的非响应者。涉及组合疗法的新型动作治疗方案的发展可以证明是治疗更多RA患者的成功。我们研究了酪氨酸激酶抑制剂（TKIS）Dasatinib和Bosutinib对人TNF依赖性TG197关节炎小鼠模型的影响。抑制剂作为单疗法或与副治疗剂量的抗HTNF生物学剂组合给药，并且它们的治疗效果在临床上，组织病理学以及通过基因表达分析评估，并与有效的TNF单疗法进行比较。达沙替尼和较小程度上，博斯托替尼抑制了来自有动力学滑膜成纤维细胞的TNF和促炎趋化因子的产生。达沙替尼，但不是Bosutinib，也很重要，以剂量依赖性方式进行了显着的方式TG197关节炎的临床和组织病理迹象。达沙替尼与次管剂量的抗HTNF生物制剂的组合导致了废除所有关节炎症状的协同抑制效果。 TG197小鼠全关节组织的基因表达分析显示，与施用作为单一疗法的治疗相比，达斯替尼与嗜碱性剂量的低次管剂量的组合最有效地将病原基因表达谱恢复到健康状态的情况下。我们的研究结果表明，Dasatinib在TNF驱动的关节炎中表现出治疗效果，可以用次管抗HTNF剂量的协同作用，以有效治疗病理学的临床和组织病理学迹象。 Dasatinib和抗HTNF的组合表现出不同的作用模式，在恢复有动力学基因签名与健康概况的特征。组合疗法与激酶抑制剂和抗TNF药剂的潜在临床应用可以为高剂量的抗HTNF单药治疗提供有趣的替代品，并增加对治疗的患者的数量增加。

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