Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo
Imatinib mesylate inhibits T-cell proliferation in vitro and delayed-type hypersensitivity in vivo
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DOI：
10.1182/blood-2003-12-4266
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发表时间：
2004-08-15
期刊：
影响因子：
20.3
通讯作者：
Vuk-Pavlovi, S
中科院分区：
文献类型：
--
作者：
Dietz, AB;Souan, L;Vuk-Pavlovi, S
甲磺酸伊马替尼（ST1571，伊马替尼）抑制同种异体成熟树突状细胞或植物血凝素（PHA）刺激的原代人T细胞DNA合成，但不诱导细胞凋亡。抑制树突状细胞和PHA刺激t细胞增殖50% （IC50）的浓度分别为3.9 muM和2.9 muM，即在甲甲酸伊马替尼治疗患者的浓度范围内。有趣的是，甲甲酸伊马替尼没有抑制t细胞活化标志物CD25和CD69的表达，尽管它降低了活化的核因子- kappab （NF-kappaB）的水平，改变了Lck、ERK1/2、视网膜母细胞瘤蛋白和细胞周期蛋白D3的磷酸化或蛋白水平。当T细胞不含甲磺酸伊马替尼时，它们对PHA产生增殖反应，表明抑制是可逆的。甲磺酸伊马替尼治疗导致细胞在细胞周期的G(0)/G(1)期积累。体外观察结果在小鼠迟发性超敏反应（DTH）模型中得到了证实。在甲磺酸伊马替尼治疗的小鼠中，与假注射对照组相比，DTH减少。然而，脾T细胞数量没有减少，这表明，与体外观察相似，甲磺酸伊马替尼抑制T细胞反应，但不引起细胞凋亡。这些发现表明，长期服用大剂量甲磺酸伊马替尼可能会影响免疫力。(C) 2004年由美国血液病学会出版。
Imatinib mesylate (ST1571, imatinib) inhibited DNA synthesis in primary human T cells stimulated with allogeneic mature dendritic cells or phytohemagglutinin (PHA) but did not induce apoptosis. The values for the concentration that inhibits 50% (IC50) of T-cell proliferation stimulated by dendritic cells and PHA were 3.9 muM and 2.9 muM, respectively, that is, within the concentration range found in patients treated with imatinib mesylate. Interestingly, imatinib mesylate did not inhibit expression of T-cell activation markers CD25 and CD69, although it reduced the levels of activated nuclear factor-kappaB (NF-kappaB) and changed phosphorylation or protein levels of Lck, ERK1/2, retinoblastoma protein, and cyclin D3. When T cells were washed free of imatinib mesylate, they proliferated in response to PHA, demonstrating that inhibition is reversible. Treatment with imatinib mesylate led to accumulation of the cells in G(0)/G(1) phase of the cell cycle. The in vitro observations were confirmed in vivo in a murine model of delayed-type hypersensitivity (DTH). In mice treated with imatinib mesylate, DTH was reduced in comparison to sham-injected controls. However, the number of splenic T cells was not reduced showing that, similarly to in vitro observations, imatinib mesylate inhibited T-cell response, but did not cause apoptosis. These findings indicate that longterm administration of high-dose imatinib mesylate might affect immunity. (C) 2004 by The American Society of Hematology.