Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro
Imatinib inhibits the activation and proliferation of normal T lymphocytes in vitro
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DOI：
10.1038/sj.leu.2403401
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发表时间：
2004-08-01
期刊：
影响因子：
11.4
通讯作者：
Dazzi, F
中科院分区：
文献类型：
--
作者：
Cwynarski, K;Laylor, R;Dazzi, F
ABL酪氨酸激酶抑制剂甲磺酸伊马替尼在治疗CML方面非常有效，并且越来越多地用于干细胞移植（SCT）。由于依赖abl的细胞内信号分子参与t细胞活化，伊马替尼可能在体内影响t细胞反应，从而影响CML患者的t细胞功能，破坏同种异体SCT后的免疫重建和/或阻碍移植物抗白血病作用。在这里，我们证明伊马替尼在体外浓度（1-5 μ mol/l）下抑制pha诱导的正常外周血单个核细胞的增殖，代表体内治疗使用的药理学剂量。这种作用不依赖于抗原呈递细胞，因为CD3/CD28诱导的t细胞刺激同样被伊马替尼抑制。同样观察到纯化的CD8（+）和CD4(+) T淋巴细胞对抗cd3 /CD28的增殖反应的剂量依赖性抑制，并与ifn - γ产生的减少有关。伊马替尼（1-5 μ mol/L）可显著降低CD3(+) T细胞上活化标记物的表达。从培养物中去除药物后，t细胞增殖的抑制是可逆的。因此，伊马替尼在体外抑制t细胞增殖，这种作用与apc无关，可逆，不涉及细胞凋亡诱导。
The ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of CML and is increasingly used in the stem cell transplantation (SCT) setting. Since ABL-dependent intracellular signaling molecules are involved in T-cell activation, imatinib may affect T-cell responses in vivo, thus affecting T-cell function in CML patients, disrupting immune reconstitution after allogeneic SCT and/or impeding the graft-versus-leukemia effect. Here we demonstrate that imatinib inhibits PHA-induced proliferation of normal peripheral blood mononuclear cells at in vitro concentrations (1-5 mumol/l) representative of the pharmacological doses used therapeutically in vivo. The effect is not dependent on antigen-presenting cells because CD3/CD28- induced T-cell stimulation was similarly inhibited by imatinib. Dose-dependent inhibition of the proliferative response of purified CD8(+) and CD4(+) T lymphocytes to anti-CD3/CD28 was similarly observed and associated with reduction in IFN-gamma production. The inhibitory effect could not be ascribed to an increased rate of apoptosis but the expression of activation markers on CD3(+) T cells was significantly reduced in the presence of imatinib (1-5 mumol/L). Inhibition of T-cell proliferation was reversible after removal of the drug from the cultures. Thus, imatinib inhibits T-cell proliferation in vitro, an effect that is APC-independent, reversible, and does not involve apoptosis induction.