Eisenthal A, Cameron R B, Rosenberg S A
Surgery Branch, National Cancer Institute, Bethesda, MD 20892.
J Immunol. 1990 Jun 1;144(11):4463-71.
We have previously shown the ability of different cytokines to induce antibody-dependent cellular cytotoxicity (ADCC) in murine cells in vitro. In addition we found that the administration to mice of IL-2-induced cells which mediated ADCC and that these cells were phenotypically similar to the cells induced in vitro. In the present study we tested the ability of various cytokines, including IL-1, TNF, IFN-alpha, and IFN-gamma to induce ADCC in vivo. We found that both IFN-alpha and IFN-gamma induced ADCC in the livers and spleens of C3H/Hen-treated mice and that these cytokines together with TNF enhanced the IL-2-induced ADCC in vivo. In C57BL/6 mice which, as previously shown, exhibit relatively low ADCC activity, IFN-alpha and IFN-gamma increased the IL-2-induced ADCC only when 100,000 U of IL-2 were used for priming. The effect of IFN-alpha on ADCC was dose dependent and was optimal after the administration of 200,000 U of the cytokine given three times a day for 3 days. Similar to the cells induced in vivo by IL-2, the precursors of the cells mediating ADCC were asialo GM1+ whereas the effectors were mainly nonadherent, Thy-1+ cells. IFN-alpha-generated cells mediating ADCC in the liver and spleen and, when combined with IL-2, ADCC was induced in the thymus as well. This effect of IFN-alpha on the induction of ADCC was exploited in an immunotherapy model in which we found that IFN-alpha significantly enhanced the antibody-mediated antitumor effect on established B16 melanoma liver micrometastases. Furthermore, when IL-2 and IFN-alpha administration was combined with the administration of mAb, a significantly reduced number of established 6- to 8-day B16 melanoma liver macrometastases and prolonged survival of tumor-bearing mice were seen. These studies imply that the administration of appropriate cytokine combinations may be a useful adjunct to the administration of mAb for the treatment of cancer in humans.
我们之前已经证明了不同细胞因子在体外诱导小鼠细胞产生抗体依赖性细胞毒性（ADCC）的能力。此外，我们发现给小鼠注射介导ADCC的IL-2诱导细胞，并且这些细胞在表型上与体外诱导的细胞相似。在本研究中，我们测试了包括IL-1、TNF、IFN-α和IFN-γ在内的各种细胞因子在体内诱导ADCC的能力。我们发现IFN-α和IFN-γ均可在C3H/Hen处理的小鼠肝脏和脾脏中诱导ADCC，并且这些细胞因子与TNF一起可增强体内IL-2诱导的ADCC。在如之前所示表现出相对较低ADCC活性的C57BL/6小鼠中，仅当使用100,000 U的IL-2进行预刺激时，IFN-α和IFN-γ才会增加IL-2诱导 的ADCC。IFN-α对ADCC的作用呈剂量依赖性，在每天三次给予200,000 U细胞因子，连续给药3天时效果最佳。与IL-2在体内诱导的细胞相似，介导ADCC的细胞前体是无唾液酸GM1+，而效应细胞主要是非黏附性的Thy-1+细胞。IFN-α在肝脏和脾脏中产生介导ADCC的细胞，并且当与IL-2联合使用时，在胸腺中也可诱导ADCC。IFN-α对ADCC诱导的这种作用被应用于一种免疫治疗模型中，我们发现在该模型中IFN-α可显著增强抗体介导的对已形成的B16黑色素瘤肝微转移的抗肿瘤作用。此外，当IL-2和IFN-α的给药与单克隆抗体（mAb）的给药相结合时，可观察到已形成的6至8天B16黑色素瘤肝大转移灶数量显著减少，荷瘤小鼠的生存期延长。这些研究表明，给予适当的细胞因子组合可能是在人类癌症治疗中给予mAb的一种有用辅助手段。
