Ohmi Y, Shiku H, Nishimura T
Section of Genetic Engineering, Research Center for Genetic Engineering and Cell Transplantation, Tokai University School of Medicine, Bohseidai, Isehara 259-1193, Japan.
Cancer Immunol Immunother. 1999 Nov;48(8):456-62. doi: 10.1007/s002620050622.
T helper type1 (Th1) or type2 (Th2) cells were induced from naive Th cells obtained from ovalbumin-specific T cell receptor (TCR) transgenic mice. Th1 cells producing interferon gamma (IFNgamma) exhibited stronger antigen-specific cytotoxicity against ovalbumin-(323-339)-peptide-pulsed A20 tumor cells than did Th2 cells. To develop a general method for applying antigen-nonspecific Th1 cells to tumor immunotherapy, we examined the targeting of Th1 cells to tumor cells using a bispecific antibody (bsAb) consisting of anti-(mouse CD3) mAb and anti-(human c-ErbB-2) mAb. When ovalbumin-specific Th1 or Th2 cells were cocultured with c-erbB-2-positive transfectants (CMS7HE), neither type of cell showed significant cytotoxicity or cytokine production in response to tumor cells. However, addition of bsAb resulted in the triggering of both Th1 and Th2 cells. Th1 cells showed higher levels of bsAb-dependent cytotoxicity against CMS7HE tumor cells than did Th2 cells. The targeting of Th1 cells to CMS7HE tumor cells by bsAb also triggered the production of cytokines such as IFNgamma, interleukin-2 and tumor necrosis factor alpha (TNFalpha). The released TNFalpha was demonstrated to be a critical cytolytic factor in bsAb-mediated cytotoxicity by Th1 cells. Finally, Th1 cells were demonstrated to show antitumor activity in vivo against human c-erbB-2-positive tumor cells implanted in nude mice. These results suggest that Th1 cells are useful effector cells for the application to adoptive tumor immunotherapy in conjunction with bsAb.
从卵清蛋白特异性T细胞受体（TCR）转基因小鼠获得的初始Th细胞诱导分化为1型辅助性T细胞（Th1）或2型辅助性T细胞（Th2）。产生干扰素γ（IFNγ）的Th1细胞对经卵清蛋白-（323-339）-肽脉冲处理的A20肿瘤细胞表现出比Th2细胞更强的抗原特异性细胞毒性。为了开发一种将抗原非特异性Th1细胞应用于肿瘤免疫治疗的通用方法，我们使用由抗（小鼠CD3）单克隆抗体和抗（人c-ErbB-2）单克隆抗体组成的双特异性抗体（bsAb）研究了Th1细胞对肿瘤细胞的靶向作用。当卵清蛋白特异性Th1或Th2细胞与c-erbB-2阳性转染细胞（CMS7HE）共培养时，两种细胞对肿瘤细胞均未表现出明显的细胞毒性或细胞因子产生。然而，添加bsAb会触发Th1和Th2细胞。Th1细胞对CMS7HE肿瘤细胞的bsAb依赖性细胞毒性水平高于Th2细胞。bsAb将Th1细胞靶向CMS7HE肿瘤细胞也触发了细胞因子如IFNγ、白细胞介素-2和肿瘤坏死因子α（TNFα）的产生。释放的TNFα被证明是Th1细胞介导的bsAb细胞毒性中的关键溶细胞因子。最后，Th1细胞在体内对植入裸鼠的人c-erbB-2阳性肿瘤细胞显示出抗肿瘤活性。这些结果表明，Th1细胞是与bsAb联合应用于过继性肿瘤免疫治疗的有用效应细胞。
