Aoki H, Mizuno M, Natsume A, Tsugawa T, Tsujimura K, Takahashi T, Yoshida J
Department of Neurosurgery, Nagoya University Graduate School of Medicine, Japan.
Cancer Immunol Immunother. 2001 Nov;50(9):463-8. doi: 10.1007/s002620100220.
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that locate in peripheral organs. It has been thought that a systemic immune response does not play a role in regression of central nervous system (CNS) tumors, because the CNS is an immunologically privileged site. However, recent advances in immunology have led to the possibility of immunotherapy using peripheral DCs against CNS tumors. Here, we investigated whether DCs pulsed with tumor extract could induce an antitumor effect against malignant glioma. Furthermore, we also investigated whether the antitumor effect become higher by pulsation with tumor extract-liposome complex, compared to pulsation with tumor extract alone. As a liposome, we used cationic small unilamellar vesicles composed of N-(alpha-trimethylammonioacetyl)-didodecyl-D-glutamate chloride (TMAG), dilauroylphosphatidylcholine (DLPC), and dioleoylphosphatidylethanolamine (DOPE) in a molar ratio of 1:2:2. After intracerebral inoculation of mouse malignant glioma GL261 cells into syngeneic C57BL/6 mice, DCs pulsed with extract from the glioma cells by sonication were administered intraperitoneally thrice weekly on days 7, 14 and 21. Tumor growth inhibition was evaluated by measuring the tumor size 1 month after the tumor inoculation. The group treated with DCs pulsed by tumor extract was inhibited in tumor progression compared with the control non-pulsed DCs group, and the group treated with DCs pulsed by tumor extract and liposomes showed substantial tumor volume reductions in all the mice. Among the mice, there were several with no visible masses in their brains. Immunohistochemical study showed that the CD8-positive cytotoxic T cells (CTLs) were strongly recognized among the almost disappearing tumor cells of pulsed DCs groups. The CTLs showed a specific antitumor activity for GL261 mouse glioma cells. These findings indicated that DCs pulsed with tumor extract and liposomes might play an important role in the activation of an immune response in malignant glioma.
树突状细胞（DCs）是位于外周器官的专职抗原呈递细胞（APCs）。人们一直认为，全身免疫反应在中枢神经系统（CNS）肿瘤的消退中不起作用，因为中枢神经系统是一个免疫特惠部位。然而，免疫学的最新进展使得利用外周DCs进行中枢神经系统肿瘤免疫治疗成为可能。在此，我们研究了用肿瘤提取物脉冲处理的DCs是否能诱导针对恶性胶质瘤的抗肿瘤作用。此外，我们还研究了与单独用肿瘤提取物脉冲处理相比，用肿瘤提取物-脂质体复合物脉冲处理是否能增强抗肿瘤作用。作为脂质体，我们使用了由N-（α-三甲基铵乙酰基）-二癸基-D-谷氨酸氯（TMAG）、二月桂酰磷脂酰胆碱（DLPC）和二油酰磷脂酰乙醇胺（DOPE）按1:2:2的摩尔比组成的阳离子小单层囊泡。将小鼠恶性胶质瘤GL261细胞脑内接种到同基因C57BL/6小鼠后，在第7、14和21天每周三次腹腔注射经超声处理的胶质瘤细胞提取物脉冲处理的DCs。通过在肿瘤接种1个月后测量肿瘤大小来评估肿瘤生长抑制情况。与未脉冲处理的对照DCs组相比，用肿瘤提取物脉冲处理的DCs组的肿瘤进展受到抑制，用肿瘤提取物和脂质体脉冲处理的DCs组的所有小鼠的肿瘤体积均显著减小。在这些小鼠中，有几只脑内没有可见肿块。免疫组织化学研究表明，在脉冲处理的DCs组几乎消失的肿瘤细胞中，CD8阳性细胞毒性T细胞（CTLs）被强烈识别。CTLs对GL261小鼠胶质瘤细胞表现出特异性抗肿瘤活性。这些发现表明，用肿瘤提取物和脂质体脉冲处理的DCs可能在恶性胶质瘤免疫反应的激活中起重要作用。
