Kurzawa H, Wysocka M, Aruga E, Chang A E, Trinchieri G, Lee W M
Cell and Molecular Biology Graduate Group, Philadelphia, Pennsylvania 19104, USA.
Cancer Res. 1998 Feb 1;58(3):491-9.
Adjuvant use of recombinant murine IL-12 (rmIL-12) was examined in mice vaccinated with irradiated syngeneic tumor or allogeneic cells. rmIL-12 given to A/J mice vaccinated with irradiated SCK tumor cells engineered to secrete granulocyte/macrophage-colony-stimulating factor resulted in significantly better protection from tumor challenges 28 days after vaccination but, unexpectedly, severely compromised host protection 14 days after vaccination. Immune suppression was rmIL-12 dose dependent and manifested as reduced splenic CTL activity, stimulated cytokine release and ability to reject SCK cells. Transient immune suppression was also seen with rmIL-12 given during vaccination of C3H/HeN mice with irradiated K1735 melanoma cells and of C57BL/6 mice with irradiated allogeneic HKB cells. The period of suppression coincided with transiently reduced splenic T-cell mitogenic responses to concanavalin A and IL-2, suggesting that they may be causally related. Suppression appears to be due to impaired immune effector mechanisms rather than impaired host immunization, which is actually enhanced as evidenced by the enhanced reaction to immunogens when hosts are challenged later after rmIL-12 administration. Demonstration that rmIL-12, as it is frequently used, induces a transient period of impaired immune response that can compromise host protection suggests that the unquestioned effectiveness of rmIL-12 against murine tumors is primarily due to activation of mechanisms other than antigen-specific tumor immunity (e.g., antiangiogenic effects) and that use of human IL-12 should be monitored for similar effects.
在接种了经辐照的同基因肿瘤细胞或异基因细胞的小鼠中，研究了重组鼠白细胞介素-12（rmIL-12）的辅助作用。给接种了经辐照的、经基因工程改造以分泌粒细胞/巨噬细胞集落刺激因子的SCK肿瘤细胞的A/J小鼠注射rmIL-12，在接种后28天能显著增强对肿瘤攻击的保护作用，但出乎意料的是，在接种后14天会严重损害宿主的保护作用。免疫抑制呈rmIL-12剂量依赖性，表现为脾细胞CTL活性降低、刺激的细胞因子释放减少以及排斥SCK细胞的能力下降。在用经辐照的K1735黑色素瘤细胞接种C3H/HeN小鼠以及用经辐照的异基因HKB细胞接种C57BL/6小鼠的过程中给予rmIL-12，也观察到了短暂的免疫抑制。抑制期与脾细胞对伴刀豆球蛋白A和IL-2的促有丝分裂反应短暂降低相吻合，这表明它们可能存在因果关系。抑制似乎是由于免疫效应机制受损，而非宿主免疫受损，实际上宿主免疫是增强的，这可通过在给予rmIL-12后较晚时间对宿主进行免疫原攻击时反应增强得到证明。rmIL-12在常用时会诱导一段短暂的免疫反应受损期，从而可能损害宿主保护作用，这一发现表明，rmIL-12对鼠肿瘤的显著疗效主要是由于激活了抗原特异性肿瘤免疫以外的机制（如抗血管生成作用），并且在使用人IL-12时应监测是否有类似效应。
