An analysis for mechanism of antitumor effects of IL-18 and a clinical application of IL-18 for head and neck tumors

IL-18抗肿瘤作用机制分析及IL-18治疗头颈部肿瘤的临床应用

基本信息

批准号：
12671921
负责人：
ECHIGO Seishi
金额：
$ 2.11万
依托单位：
TOHOKU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671921/
关键词：
IL-18 antitumor effect NK cells IFN-γ IL-12 dendritic cells innate immunity specific immunity CTL

项目摘要

To clarify the antitumor effects of interleukin 18 (IL-18), an effector mechanism of IL-18 was analyzed in murine tumor model. We revealed that NK cells but not NKT cells play a necessary role to promote an innate antitumor response induced by IL-18. Moreover, we hypothesized that antitumor-specific immunity, which is induced by IL-18 treatment in murine tumor models, is promoted by enhancing NK-mediated destruction of tumor and delivery to dendritic cells (DCs). We assesed the effect of IL-18 added to cultures of live tumor cells, NK cells, DCs, and T cells and revealed that IL-18 induces tumor-specific immunity through enhancing NK activity, which in turn mediates tumor cell death and activates and primes DCs.Next, we investigated the in vitro effects of combining IL-18 and IL-2 on human lymphocytes. The combined use of these two cytokines synergistically enhanced IFN-γ production. Phenotypic analysis revealed a preferential expansion of CD56+ CD3- (NK) cells. To reveal that human lymphocytes activated by IL-18 induce tumor apoptosis, tumor cells were stained with Annexin-V, PhiPhiLux, or PI after 8 hours culture with lymphocytes activated by IL-18. Apoptosis of tumor cells were observed on combined use of these cytokines. These results revealed that IL-18 induces antitumor effects in human system. Therefore, the combined use of IL-2 and IL-18 should be considered a voable strategy for the generation of antitumor responses in vivo and for future clinical applications.

为了阐明白细胞介素 18 (IL-18) 的抗肿瘤作用，我们在小鼠肿瘤模型中分析了 IL-18 的效应机制，结果表明 NK 细胞而非 NKT 细胞在促进 IL 诱导的先天抗肿瘤反应中发挥着必要的作用。 -18.此外，我们发现，在小鼠肿瘤模型中，IL-18 治疗诱导的抗肿瘤特异性免疫是通过增强 NK 介导的肿瘤破坏和递送至树突状细胞而得到促进的。我们评估了添加到活肿瘤细胞、NK 细胞、DC 和 T 细胞培养物中的 IL-18 的作用，发现 IL-18 通过增强 NK 活性诱导肿瘤特异性免疫，进而介导肿瘤细胞。接下来，我们研究了联合使用 IL-18 和 IL-2 对人类淋巴细胞的体外影响，这两种细胞因子的联合使用可协同增强 IFN-γ 的产生。表型分析显示 CD56+ CD3- (NK) 细胞优先扩增为了揭示 IL-18 激活的人淋巴细胞诱导肿瘤细胞凋亡，在与 IL-18 激活的淋巴细胞培养 8 小时后，用膜联蛋白-V、PhiPhiLux 或 PI 对肿瘤细胞进行染色。联合使用这些细胞因子观察到IL-18的凋亡。这些结果表明IL-18在人体系统中诱导抗肿瘤作用。 IL-2 和 IL-18 应被视为产生体内抗肿瘤反应和未来临床应用的可行策略。