Okaji Yurai, Tsuno Nelson Hirokazu, Kitayama Joji, Saito Shinsuke, Takahashi Tsuyoshi, Kawai Kazushige, Yazawa Kentaro, Asakage Masahiro, Hori Nobukazu, Watanabe Toshiaki, Shibata Yoichi, Takahashi Koki, Nagawa Hirokazu
Department of Surgical Oncology, Graduate School of Medical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Cancer Sci. 2004 Jan;95(1):85-90. doi: 10.1111/j.1349-7006.2004.tb03175.x.
Overcoming immune tolerance of tumor angiogenesis should be useful for adjuvant therapy of cancer. We hypothesized that vaccination with autologous endothelium would induce an autoimmune response targeting tumor angiogenesis. To test this concept, we immunized BALB/c mice with a vaccine of glutaraldehyde-fixed murine hepatic sinusoidal endothelial cells (HSEs) in a lung metastasis model of Colon-26 cancer. Vaccination with autologous HSEs induced both preventive and therapeutic anti-tumor immunity that significantly inhibited the development of metastases. ELISA revealed an immunoglobulin response involving IgM and IgG subclasses. These antibodies had a strong affinity for antigens of both murine and human endothelium, and lyzed endothelial cells in the CDC assay. Flow-cytometry and chromium-release cytotoxicity assay revealed a specific CTL response against endothelial cells, which were lyzed in an effector: target ratio-dependent manner. Neither antibodies nor CTLs reacted with Colon-26. The effect of autologous HSEs was more pronounced than that of xenogeneic human umbilical vein endothelial cells (HUVECs), which were tested in the same experimental setting. Our results suggest that vaccination with autologous endothelium can overcome peripheral tolerance of self-angiogenic antigens and therefore should be useful for adjuvant immunotherapy of cancer.
克服肿瘤血管生成的免疫耐受对癌症辅助治疗应具有重要意义。我们推测，用自体内皮细胞进行疫苗接种会引发针对肿瘤血管生成的自身免疫反应。为验证这一概念，我们在结肠癌Colon - 26肺转移模型中，用戊二醛固定的小鼠肝窦内皮细胞（HSEs）疫苗免疫BALB/c小鼠。用自体HSEs进行疫苗接种可诱导预防性和治疗性抗肿瘤免疫，显著抑制转移灶的形成。酶联免疫吸附测定（ELISA）显示存在涉及IgM和IgG亚类的免疫球蛋白反应。这些抗体对小鼠和人内皮细胞的抗原均具有高亲和力，并在补体依赖的细胞毒性（CDC）试验中裂解内皮细胞。流式细胞术和铬释放细胞毒性试验显示出针对内皮细胞的特异性细胞毒性T淋巴细胞（CTL）反应，其以效应细胞与靶细胞比例依赖的方式裂解内皮细胞。抗体和CTL均不与Colon - 26发生反应。在相同实验条件下进行测试时，自体HSEs的效果比异种人脐静脉内皮细胞（HUVECs）更显著。我们的结果表明，用自体内皮细胞进行疫苗接种可克服自身血管生成抗原的外周耐受，因此对癌症辅助免疫治疗应具有重要意义。
