JAK3和BTK抑制剂抗ConA介导的小鼠重症肝炎的作用及其药靶效应

Severe hepatitis is an important healthy problem with high mortality. Finding effective immunomodulatory agents is crucial to reduce the mortality of severe hepatitis. JAK3 and BTK play an important role in the pathogenesis of inflammatory diseases since both of them are key molecules that connect innate and adaptive immunity. And JAK3 and BTK are validated targets of immune-mediated disease, such as rheumatoid arthrtis, X-lined agammaglobulinemia. Comprehensive literature suggests, JAK3 and BTK may participate in the pathogenesis of severe hepatitis through regulate inflammatory signaling pathways and immune cell function. Our study found that JAK3 and BTK was abnormally high expression in the PBMCs （Peripheral Blood Mononuclear Cells）of patients with severe hepatitis. That indicate JAK3 and BTK may participate the inflammation progress. Then we use ConA induced mouse severe hepatitis model to test the effect of JAK3 inhibitor tofacitinib, BTK inhibitor ibrutinib and new drug AC0025 which can dual target on JAK3/BTK, found that these three inhibitors can significantly reduce liver inflammation and liver damage. Above results suggested that these two important therapeutic drug targets in the pathogenesis of severe hepatitis and as effect, and having a synergistic anti-inflammatory effects. The project intends to study targeting JAK3 and BTK inhibitor anti- ConA -induced severe hepatitis and its molecular mechanism, in order to clarify their role in the pathogenesis of severe hepatitis, verify its feasibility as drug therapy targets for clinical prevention and treatment of severe hepatitis and provide new ways of thinking.

寻找有效的免疫调节剂对降低重型肝炎的病死率至关重要。JAK3和BTK在多种炎症性疾病的发病和抗炎治疗中具有重要作用。综合文献提示，JAK3和BTK可能通过调节炎性信号途径以及免疫细胞功能，参与重症肝炎的免疫发病机制。我们研究发现，在重型肝炎患者外周血淋巴细胞中，JAK3和BTK呈异常高表达；在ConA诱导的急性重症肝炎小鼠模型中，利用JAK3抑制剂tofacitinib和BTK抑制剂ibrutinib以及作用于JAK3/BTK双靶点的新药AC0025进行防治，几种抑制剂均能显著减轻肝脏炎症和肝损伤，以双靶点抑制剂的疗效最佳，提示这两个分子在重症肝炎发病及作为治疗药靶的重要作用，并具有协同抗炎效应。本项目拟研究JAK3和BTK的靶向抑制剂在抗ConA诱导的重症肝炎中的作用及其分子机制，明确它们在重症肝炎发病机制中的作用，验证其作为药物治疗靶点的可行性，为临床重症肝炎防治提供全新的方法和思维。

寻找有效的免疫调节剂对降低重型肝炎的病死率至关重要。JAK3和BTK在多种炎症性疾病的发病和抗炎治疗中具有重要作用。综合文献提示，JAK3和BTK可能通过调节炎性信号途径以及免疫细胞功能，参与重症肝炎的免疫发病机制。我们前期研究发现，在重型肝炎患者外周血淋巴细胞中，JAK3和BTK呈异常高表达；在ConA诱导的急性重症肝炎小鼠模型中，利用JAK3抑制剂Tofacitinib和BTK抑制剂Ibrutinib以及作用于JAK3/BTK双靶点的新药AC0025进行防治，几种抑制剂均能显著减轻肝脏炎症和肝损伤，以双靶点抑制剂的疗效最佳，提示这两个分子在重症肝炎发病及作为治疗药靶的重要作用，并具有协同抗炎效应。在项目实施过程中，本课题组首先通过药物的动物体内实验，用不同的药物剂量预处理小鼠后利用ConA建立急性重症肝炎模型，单独或联合应用JAK3和BTK靶向抑制剂均显示显著的肝脏保护作用，并具有良好的药物剂量依赖效应，JAK3和BTK作为抗重症肝炎药靶具有良好的可行性并具有协同效应。其后，我们确认了BTK在临床各种肝病患者PBMCs中表达量与炎症严重程度成正比，而和正常人相比，重症肝炎患者肝组织中表达明显升高，BTK可作为评价肝脏炎症状态的一个新指标。进一步研究表明，通过抑制BTK可抑制LPS介导的单核/巨噬细胞多种细胞因子的分泌，维持肝脏免疫微环境的稳定。通过本项目的实施，阐明了JAK3和BTK的靶向抑制剂在抗ConA诱导的重症肝炎中的作用及其分子机制，其作为重症肝炎药物治疗靶点具有良好的可行性与有效性，为临床重症肝炎防治提供全新的方法和思维。