Transplant and Stem Cell Immunobiology Laboratory, University Heart Center Hamburg, Hamburg, Germany.
Transplantation. 2012 Oct 15;94(7):695-702. doi: 10.1097/TP.0b013e3182660496.
Selective inhibition of lymphocyte activation through abrogation of signal 3-cytokine transduction emerges as a new strategy for immunosuppression. This is the first report on the novel Janus kinase (JAK)1/3 inhibitors R507 and R545 for prevention of acute allograft rejection.
Pharmacokinetic and in vitro enzyme inhibition assays were performed to characterize the drugs. Heterotopic Brown Norway-Lewis heart transplantations were performed to study acute cardiac allograft rejection, graft survival, suppression of cellular host responsiveness, and antibody production. Therapeutic and subtherapeutic doses of R507 (60 and 15 mg/kg 2 times per day) and R545 (20 and 5 mg/kg 2 times per day) were compared with those of tacrolimus (Tac; 4 and 1 mg/kg once per day).
Plasma levels of R507 and R545 were sustained high for several hours. Cell-based enzyme assays showed selective inhibition of JAK1/3-dependent pathways with 20-fold or greater selectivity over JAK2 and Tyrosine kinase 2 kinases. After heart transplantation, both JAK1/3 inhibitors reduced early mononuclear graft infiltration, even significantly more potent than Tac. Intragraft interferon-γ release was significantly reduced by R507 and R545, and for interleukin-10 suppression, they were even significantly more potent than Tac. Both JAK1/3 inhibitors and Tac were similarly effective in reducing the host Th1 and Th2, but not Th17, responsiveness and similarly prevented donor-specific immunoglobulin M antibody production. Subtherapeutic and therapeutic R507 and R545 doses prolonged the mean graft survival and were similarly effective as 1 and 4 mg/kg Tac, respectively. In combination regimens, however, only R507 showed highly beneficial synergistic drug interactions with Tac.
Both R507 and R545 are potent novel immunosuppressants with favorable pharmacokinetics and high JAK1/3 selectivity, but only R507 synergistically interacts with Tac.
通过阻断信号 3-细胞因子转导来选择性抑制淋巴细胞激活，这是一种新的免疫抑制策略。这是首例报道新型 Janus 激酶（JAK）1/3 抑制剂 R507 和 R545 预防急性同种异体移植物排斥反应的研究。
进行药代动力学和体外酶抑制测定以对药物进行表征。进行异位布朗-挪威-刘易斯心脏移植以研究急性心脏同种异体移植物排斥、移植物存活、抑制细胞宿主反应性和抗体产生。R507（60 和 15mg/kg，每日 2 次）和 R545（20 和 5mg/kg，每日 2 次）的治疗和亚治疗剂量与他克莫司（Tac；每日 1 次，4 和 1mg/kg）进行比较。
R507 和 R545 的血浆水平可持续数小时保持高水平。基于细胞的酶测定显示，JAK1/3 依赖性途径的选择性抑制作用比 JAK2 和酪氨酸激酶 2 激酶高 20 倍或更高。心脏移植后，两种 JAK1/3 抑制剂均减少早期单核细胞移植物浸润，甚至比 Tac 更有效。R507 和 R545 显著降低了移植物内干扰素-γ的释放，并且在抑制白细胞介素-10 方面，它们甚至比 Tac 更有效。两种 JAK1/3 抑制剂和 Tac 同样有效降低宿主 Th1 和 Th2 反应，但不能降低 Th17 反应，并且同样可以防止供体特异性免疫球蛋白 M 抗体的产生。亚治疗和治疗剂量的 R507 和 R545 可延长平均移植物存活时间，与 1 和 4mg/kg Tac 分别相当。然而，在联合方案中，只有 R507 与 Tac 表现出高度有益的协同药物相互作用。
R507 和 R545 均为强效新型免疫抑制剂，具有良好的药代动力学特性和高 JAK1/3 选择性，但只有 R507 与 Tac 具有协同相互作用。
