Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors.
Imatinib mesylate inhibits CD4+ CD25+ regulatory T cell activity and enhances active immunotherapy against BCR-ABL- tumors.
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DOI：
10.4049/jimmunol.181.10.6955
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发表时间：
2008-11-15
影响因子：
4.4
通讯作者：
Katsanis, Emmanuel
中科院分区：
文献类型：
--
作者：
Larmonier, Nicolas;Janikashvili, Nona;LaCasse, Collin James;Larmonier, Claire Billerey;Cantrell, Jessica;Situ, Elaine;Lundeen, Tamara;Bonnotte, Bernard;Katsanis, Emmanuel
甲磺酸伊马替尼（Gleevec, STI571）是一种有限数量酪氨酸激酶的选择性抑制剂，已被有效用于费城染色体阳性白血病和胃肠道间质瘤的治疗。伊马替尼也可能直接影响免疫细胞。该药对CD4+和CD8+ T淋巴细胞或树突状细胞的抑制和刺激作用已被报道。在目前的研究中，我们研究了甲磺酸伊马替尼对CD4+CD25+FoxP3+调节性T细胞（Treg）的影响，Treg是促成外周耐受的关键淋巴细胞群。在临床达到的浓度下，伊马替尼在体外损害Treg免疫抑制功能和FoxP3的表达，但不影响IL-10和TGF-β的产生。伊马替尼显著降低Treg中转录因子STAT3和STAT5的激活。Treg tcr诱导的信号级联分析表明，伊马替尼抑制了ZAP70和LAT的磷酸化。证实这些观察结果，伊马替尼治疗小鼠减少Treg频率并损害其体内免疫抑制功能。此外，甲磺酸伊马替尼显著增强了树突状细胞免疫对伊马替尼耐药BCR-ABL阴性淋巴瘤的抗肿瘤免疫反应。甲磺酸伊马替尼在癌症免疫治疗中作为靶向Treg的有效免疫调节剂，可能会扩大其临床应用。
Imatinib mesylate (Gleevec, STI571), a selective inhibitor of a restricted number of tyrosine kinases, has been effectively used for the treatment of Philadelphia chromosome positive leukemias and gastrointestinal stromal tumors. Imatinib may also directly influence immune cells. Suppressive as well as stimulating effects of this drug on CD4+ and CD8+ T lymphocytes or dendritic cells have been reported. In the current study, we have investigated the influence of imatinib mesylate on CD4+CD25+FoxP3+ regulatory T cells (Treg), a critical population of lymphocytes that contributes to peripheral tolerance. Used at concentrations achieved clinically, imatinib impaired Treg immunosuppressive function and FoxP3 expression but not production of IL-10 and TGF-β in vitro. Imatinib significantly reduced the activation of the transcription factors STAT3 and STAT5 in Treg. Analysis of Treg TCR-induced signaling cascade indicated that imatinib inhibited phosphorylation of ZAP70 and LAT. Substantiating these observations, imatinib treatment of mice decreased Treg frequency and impaired their immunosuppressive function in vivo. Furthermore, imatinib mesylate significantly enhanced anti-tumor immune responses to dendritic cell-based immunization against an imatinib-resistant BCR-ABL negative lymphoma. The clinical applications of imatinib mesylate might thus be expanded with its use as a potent immunomodulatory agent targeting Treg in cancer immunotherapy.
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影响因子：
11.4
作者：
Gao, H;Lee, BN;Reuben, JM
通讯作者：
Reuben, JM
影响因子：
4.4
作者：
Pallandre, Jean-Rene;Brillard, Emilie;Borg, Christophe
通讯作者：
Borg, Christophe
影响因子：
4.4
作者：
Comes, A;Rosso, O;Ferrini, S
通讯作者：
Ferrini, S
影响因子：
5.4
作者：
Ghiringhelli, F;Larmonier, N;Martin, F
通讯作者：
Martin, F
影响因子：
3.9
作者：
Attia, P;Powell, DJ;Rosenberg, SA
通讯作者：
Rosenberg, SA