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.

为了阐明白介素18（IL-18）的抗肿瘤作用，在鼠肿瘤模型中分析了IL-18的效应机制。我们揭示了NK细胞而非NKT细胞在促进IL-18引起的先天抗肿瘤反应方面起着必要的作用。此外，我们假设通过增强NK介导的肿瘤破坏并递送到树突状细胞（DCS）来促进抗肿瘤特异性免疫，该抗肿瘤特异性免疫是由IL-18治疗诱导的。我们评估IL-18对活肿瘤细胞，NK细胞，DCS和T细胞的培养的影响，并发现IL-18通过增强NK活性诱导肿瘤特异性免疫，而NK活性又介导了肿瘤细胞死亡并激活和普遍存在的DCS.Next。这两种细胞因子的联合使用协同增强了IFN-γ的产生。表型分析表明，CD56+ CD3-（NK）细胞的首选膨胀。为了揭示IL-18激活的人淋巴细胞会影响肿瘤凋亡，在8小时培养肿瘤细胞中，用IL-18激活的淋巴细胞培养8小时后用膜联蛋白-V，菲脂或PI染色。这些细胞因子的综合使用观察到肿瘤细胞的凋亡。这些结果表明，IL-18影响人类系统中的抗肿瘤作用。因此，应将IL-2和IL-18的综合使用视为在体内和将来的临床应用中产生抗肿瘤反应的可笑策略。