Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner
Imatinib inhibits T-cell receptor-mediated T-cell proliferation and activation in a dose-dependent manner
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DOI：
10.1182/blood-2004-07-2527
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发表时间：
2005-03-15
期刊：
影响因子：
20.3
通讯作者：
Wiestner, A
中科院分区：
文献类型：
--
作者：
Seggewiss, R;Loré, K;Wiestner, A
酪氨酸激酶抑制剂伊马替尼(伊马替尼、ST1571、格列卫和格列卫)越来越多地用于白血病异基因移植的患者。然而，人们对其潜在的免疫调节作用知之甚少。在这里，我们研究了伊马替尼对T细胞受体(TCR)介导的人T细胞活化的影响。经抗CD3抗体12F6刺激后，10 mU伊马替尼几乎完全抑制活化T细胞的增殖。此外，免疫显性巨细胞病毒(CMV)和EB病毒(EBV)多肽对CD8(+)T细胞的抗原刺激作用显著降低。伊马替尼的平均抑制浓度(IC50)分别为5.4mU/M和7.3mU/L，可抑制TCR交联引起的活化标志物CD25和CD69的上调，并抑制白介素2(IL-2)的产生。对TCR诱导的信号级联的分析表明，伊马替尼显著降低了通过TCR激活的ZAP70和LAT的酪氨酸磷酸化水平。对人类基因组中所有90个酪氨酸激酶基因在三磷酸腺苷(ATP)结合口袋中的同源性进行了序列比较，确定ZAP70激活所需的LCK可能是伊马替尼的靶标。体外酪氨酸激酶实验显示，伊马替尼抑制LCK的IC50为0.6~0.8mU。综上所述，伊马替尼在体外可以干扰T细胞的激活，其对移植后机会性感染和移植物抗宿主或移植物抗白血病反应的影响应在临床试验中进行研究。(C)2005年，由美国血液病学会提供。
The tyrosine kinase inhibitor imatinib (imatinib, ST1571, Glivec, and Gleevec) is increasingly used in patients undergoing allogeneic transplantation for leukemia. However, little is known regarding its potential immunoregulatory effects. Here, we investigate the effect of imatinib on T-cell receptor (TCR)-mediated activation of human T cells. Following stimulation with the anti-CD3 antibody 12F6, proliferation of activated T cells was almost completely inhibited by 10 mu M imatinib. Furthermore, antigen-triggered expansion of CD8(+) T cells in response to immunodominant cytomegalovirus (CMV) and Epstein-Barr virus (EBV) peptides was significantly reduced. Up-regulation of the activation markers CD25 and CD69 in response to TCR cross-linking was suppressed by imatinib at a mean inhibitory concentration 50% (IC50) of 5.4 mu M and 7.3 mu M, respectively; interleukin 2 (IL-2) production was also impaired. Analysis of the TCR-induced signaling cascade showed that imatinib substantially reduced tyrosine phosphorylation of ZAP70 and LAT in response to activation through the TCR. Sequence comparisons of all 90 tyrosine kinase genes in the human genome for homology in the adenosine triphosphate (ATP) binding pocket identified LCK, which is required for ZAP70 activation, as a likely target for imatinib. The IC50 for LCK inhibition by imatinib was 0.6 mu M to 0.8 mu M in an in vitro tyrosine kinase assay. In summary, imatinib can interfere with T-cell activation in vitro, and its impact on the frequency of opportunistic infections and graft-versus-host or graft-versus-leukemia reactions after transplantation should be investigated in clinical trials. (c) 2005 by The American Society of Hematology.