Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity.
Therapeutic effect of interleukin 12 on mouse haemangiosarcomas is not associated with an increased anti-tumour cytotoxic T-lymphocyte activity.
复制标题
白细胞介素12对小鼠血管肉瘤的治疗作用与抗肿瘤细胞毒性T-淋巴细胞活性的增加无关。
DOI：
10.1038/bjc.1998.105
复制
发表时间：
1998-02
影响因子：
8.8
通讯作者：
Collavo, D
中科院分区：
文献类型：
--
作者：
Vizler, C;Rosato, A;Calderazzo, F;Quintieri, L;Fruscella, P;Wainstok de Calmanovici, R;Mantovani, A;Vecchi, A;Zanovello, P;Collavo, D
在同基因小鼠中，H5V多瘤中t癌基因转化内皮瘤细胞系诱导卡波西氏肉瘤样海绵状血管瘤短暂消退，可能是由于抗肿瘤免疫反应，但最终会逐渐生长并杀死宿主。为了评估肿瘤特异性细胞毒性T淋巴细胞（ctl）的产生，在白细胞-肿瘤细胞混合培养中，用辐照的H5V细胞重新刺激荷瘤小鼠的脾脏细胞。肿瘤特异性ctl仅在使用低数量的H5V刺激细胞（每50个脾细胞<1个H5V细胞）时被证实。我们发现H5V细胞分泌免疫抑制介质，因为当将H5V细胞培养上清添加到异体混合白细胞培养物中时，CTL的产生被阻断。由于许多肿瘤来源的免疫抑制介质可能干扰白细胞介素12 （IL-12）的产生，我们测试了IL-12治疗荷瘤小鼠是否会增强其免疫反应，从而抑制肿瘤生长。事实上，IL-12抑制肿瘤生长并防止死亡，但无论在体内还是体外，都不能增加抗h5v CTL的产生。此外，抗干扰素(IFN)- γ单克隆抗体（MAb）联合给药可消除il -12处理小鼠的抗肿瘤活性。这些结果强烈表明，IL-12的抗肿瘤作用主要是由ifn - γ释放介导的，ifn - γ释放反过来阻断H5V细胞增殖并诱导抑制血管生成的因子的释放。
In syngeneic mice, the H5V polyoma middle-T oncogene-transformed endothelioma cell line induces Kaposi's sarcoma-like cavernous haemangiomas that regress transiently, probably because of an anti-tumour immune response, but eventually grow progressively and kill the host. To evaluate the generation of tumour-specific cytotoxic T lymphocytes (CTLs), spleen cells of tumour-bearing mice were restimulated with irradiated H5V cells in mixed leucocyte-tumour cell cultures. Tumour-specific CTLs were demonstrable only when low numbers of H5V stimulator cells were used (<1 H5V cell per 50 splenocytes). We found that H5V cells secrete immunosuppressive mediators because CTL generation was blocked when H5V cells culture supernatants were added to allogeneic mixed leucocyte cultures. As numerous tumour-derived immunosuppressive mediators may interfere with interleukin 12 (IL-12) production, we tested whether IL-12 treatment of the tumour-bearing mice would augment their immune response and thus suppress tumour growth. Indeed, IL-12 inhibited tumour growth and prevented mortality, but did not increase anti-H5V CTL generation either in vitro or in vivo. Moreover, the anti-tumour activity in IL-12-treated mice was abrogated by anti-interferon (IFN)-gamma monoclonal antibody (MAb) co-administration. These results strongly suggest that the anti-tumour effect of IL-12 is principally mediated by IFN-gamma release that in turn blocks H5V cell proliferation and induces the release of factors that suppress angiogenesis.