Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors
Stimulation of TLR9 with CpG ODN enhances apoptosis of glioma and prolongs the survival of mice with experimental brain tumors
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DOI：
10.1002/glia.20401
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发表时间：
2006-11-01
期刊：
影响因子：
6.2
通讯作者：
Lesniak, Maciej S.
中科院分区：
文献类型：
--
作者：
El Andaloussi, Abdeljabar;Sonabend, Adam M.;Lesniak, Maciej S.
Toll样受体（TLR）识别一组保守的分子结构，即所谓的病原体相关分子模式，使其能够感知和启动先天性和适应性免疫应答。在这项研究中，我们研究了TLRs在人类和小鼠胶质瘤中的表达。然后，我们分析了合成的硫代磷酸寡脱氧核苷酸（ODNs）含有非甲基化的CpG二核苷酸（CpG ODNs），先天性和适应性免疫的强激活剂治疗后TLR表达的变化。此外，我们研究了CpG注射到植入同基因GL 261胶质瘤的C57 BL/6小鼠中的体内效应。我们的研究结果表明，TLR 9在人类和小鼠胶质瘤细胞系中过表达，CpG刺激降低了实验性脑肿瘤小鼠的存活率。CpG在体内和体外诱导GL 261细胞TLR 9下调，随后诱导细胞凋亡。此外，CpG刺激的作用似乎增强了小胶质细胞的抗原呈递能力，将免疫应答转向CD 8（+）T细胞，并减少了CD 4（+）CD 25（+）调节性T细胞的数量。总之，我们的数据支持CpG在胶质瘤免疫治疗中的作用，并为进一步临床开发CpG治疗恶性胶质瘤患者提供了理论基础。(c)2006威利-利斯公司
Toll-like receptors (TLRs) recognize a set of conserved molecular structures, so called pathogen-associated molecular patterns, which allow them to sense and initiate innate and adaptive immune responses. In this study, we examined the expression of TLRs in both human and murine glioma. We then analyzed the change in TLR expression after treatment with synthetic phosphorothioate oligodeoxynucleotides (ODNs) containing unmethylated CpG dinucleotides (CpG ODNs), strong activators of both innate and adaptive immunity. In addition, we investigated the in vivo effect of CpG injection into C57BL/6 mice implanted with syngeneic GL261 glioma. Our results indicate that TLR9 is overexpressed in human and murine glioma cell lines and CpG stimulation prolongs the survival of mice with experimental brain tumors. CpGs induce TLR9 down-regulation, followed by apoptosis of GL261 cells in vitro as well as in vivo. Furthermore, the effects of CpG stimulation appear to enhance the antigen presenting capacity of microglia, shift the immune response toward CD8(+) T cells, and decrease the number of CD4(+)CD25(+) regulatory T cells. Taken together, our data support the role of CpG in glioma immunotherapy and provide a rationale for further clinical development of CpG therapy in patients with malignant glioma. (c) 2006 Wiley-Liss, Inc.