Fleischmann C M, Stanton G J, Fleischmann W R
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston 77555, USA.
J Interferon Cytokine Res. 1996 Oct;16(10):805-12. doi: 10.1089/jir.1996.16.805.
Mouse B16 melanoma cells maintained in vitro in the presence of interferon (IFN)-alpha become resistant to the in vitro antiproliferative effects of IFN-alpha. However, IFN-alpha-treated mice inoculated with these in vitro IFN-treated cells (B16 alpha res cells) have significantly increased life spans (ILS) and significantly higher cure rates than IFN-alpha-treated mice inoculated with B16 cells. This unexpectedly greater sensitivity of B16 alpha res cells to the in vivo antitumor effects of IFN-alpha was evaluated by in vivo cell depletion experiments. Depletion of either activated peritoneal macrophages or cytotoxic T lymphocytes (CTL) reduced the ILS of IFN-treated B16 alpha res-inoculated mice to a level comparable to that of IFN-treated B16-inoculated mice. Depletion of natural killer (NK) cells did not affect the ILS for IFN-treated B16 alpha res-inoculated mice. These studies indicate that activated macrophage and CD8 cell function, but not NK cell function, is important for the enhanced antitumor effects induced by IFN-alpha against B16 alpha res cells. Macrophage killing was unlikely to be mediated by TNF-alpha or IL-1 as B16 and B16 alpha res cells were equally sensitive to TNF-alpha and insensitive to IL-1 in vitro. Further, H-2K antigen expression is significantly more readily inducible on B16 alpha res cells than on B16 cells, consistent with enhanced CD8-mediated killing due to increased MHC class I antigen expression.
在干扰素（IFN）-α存在的情况下体外培养的小鼠B16黑色素瘤细胞，对IFN-α的体外抗增殖作用产生抗性。然而，接种这些体外经IFN处理的细胞（B16αres细胞）的IFN-α处理小鼠，与接种B16细胞的IFN-α处理小鼠相比，其寿命显著延长（ILS）且治愈率显著更高。通过体内细胞清除实验评估了B16αres细胞对IFN-α体内抗肿瘤作用出人意料的更高敏感性。清除活化的腹腔巨噬细胞或细胞毒性T淋巴细胞（CTL），会使接种IFN处理的B16αres细胞的小鼠的ILS降低到与接种IFN处理的B16细胞的小鼠相当的水平。清除自然杀伤（NK）细胞对接种IFN处理的B16αres细胞的小鼠的ILS没有影响。这些研究表明，活化的巨噬细胞和CD8细胞功能而非NK细胞功能，对于IFN-α诱导的针对B16αres细胞的增强抗肿瘤作用很重要。巨噬细胞杀伤不太可能由TNF-α或IL-1介导，因为B16和B16αres细胞在体外对TNF-α同样敏感且对IL-1不敏感。此外，与由于MHC I类抗原表达增加导致的CD8介导的杀伤增强一致，B16αres细胞比B16细胞上H-2K抗原表达显著更容易被诱导。
