Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia
Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia
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DOI：
10.1038/sj.leu.2403933
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发表时间：
2005-11-01
期刊：
影响因子：
11.4
通讯作者：
Reuben, JM
中科院分区：
文献类型：
--
作者：
Gao, H;Lee, BN;Reuben, JM
尽管甲磺酸伊马替尼 (IM) 在诱导慢性粒细胞白血病 (CML) 患者完全细胞遗传学缓解方面非常有效，但众所周知，它在体外会抑制 T 细胞增殖。由于T细胞增殖需要细胞因子，我们通过体外评估活化的CD4(+)和CD8(+) T细胞的细胞因子合成来研究IM对CML患者T细胞合成细胞因子的影响。用葡萄球菌肠毒素 B 激活 IM 治疗患者 (CML-IM) 的全血中的 T 细胞，导致合成白细胞介素 2 (P = 0.017)、干扰素-γ (P = 0.010) 和肿瘤坏死因子-α (P = 0.009) 的 CD4(+) T 细胞百分比显着低于对照受试者的激活 T 细胞。在CML-IM患者的外周血单核细胞培养物中添加外源IM可减少CD4(+) T细胞合成Th1细胞因子。此外，临床剂量的IM治疗抑制了ZAP70的酪氨酸磷酸化。这些发现表明，CD4(+) T 细胞抑制 ZAP70 信号通路和抑制 Th1 细胞因子合成需要在 T 细胞通过 T 细胞受体激活时存在 IM。
Although imatinib mesylate (IM) is highly effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia (CML), it is known to suppress T-cell proliferation in vitro. As cytokines are required for T-cell proliferation, we investigated the effects of IM on cytokine synthesis by T cells of CML patients by assessing cytokine synthesis by activated CD4(+) and CD8(+) T cells in vitro. The activation of T cells in the whole blood of IM-treated patients (CML-IM) with Staphylococcus enterotoxin B resulted in significantly lower percentages of CD4(+) T cells that synthesized interleukin 2 (P = 0.017), interferon-gamma (P = 0.010), and tumor necrosis factor-alpha (P = 0.009) than did the activated T cells of control subjects. The addition of exogenous IM to the cultures of peripheral blood mononuclear cells of CML-IM patients reduced Th1 cytokine synthesis by the CD4(+) T cells. Furthermore, IM therapy at clinical doses suppressed the tyrosine phosphorylation of ZAP70. These findings suggest that inhibition of ZAP70 signaling pathway and suppression of Th1 cytokine synthesis by CD4(+) T cells required the presence of IM at the time of T-cell activation through the T-cell receptor.