Recombinant interleukin-12 and interleukin-18 antitumor therapy in a guinea-pig hepatoma cell implant model
Recombinant interleukin-12 and interleukin-18 antitumor therapy in a guinea-pig hepatoma cell implant model
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DOI：
10.1111/j.1349-7006.2007.00614.x
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发表时间：
2007-12-01
期刊：
影响因子：
5.7
通讯作者：
Seya, Tsukasa
中科院分区：
文献类型：
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作者：
Shiratori, Ikuo;Suzuki, Yasuhiko;Seya, Tsukasa
白细胞介素（IL）-12和IL-18由用佐剂如卡介苗（BCG）细胞壁活化的骨髓细胞分泌。它们诱导宿主免疫系统中的辅助性T细胞1极化，并上调淋巴细胞干扰素-γ的产生，从而诱导抗肿瘤基因程序。据报道，人类的免疫系统在免疫应答特征上更接近豚鼠，而不是小鼠系统，这阻止了小鼠结果外推到人类免疫治疗。本研究建立了豚鼠肿瘤移植系统，以评价豚鼠IL-12（gpIL-12）和豚鼠IL-18（gpIL-18）的抗肿瘤潜力。制备纯化的重组gpIL-12和gpIL-18，并将其腹腔内应用于荷瘤（10号肝癌系）豚鼠，作为辅助免疫治疗的基础。腹膜内给予gpIL-12和gpIL-18导致荷瘤豚鼠原发性肿瘤生长迟缓和淋巴结转移抑制。豚鼠IL-12的容许范围比小鼠宽。即使IL-12的剂量高于小鼠，直到第26天豚鼠被杀死时才有副作用的证据。gpIL-18增强了gpIL-12的抗肿瘤作用，但抑制淋巴结转移的能力较弱。gpIL-12和gpIL-18对豚鼠移植肿瘤的作用将鼓励我们使用IL-12和IL-18诱导型佐剂用于实体癌患者的免疫治疗。
Interleukin (IL)-12 and IL-18 are secreted by myeloid cells activated with adjuvants such as Bacillus Calmette-Guerin (BCG) cell wall. They induce T-helper 1 polarization in the host immune system and upregulate production of lymphocyte interferon-gamma, which leads to the induction of an antitumor gene program. It has been reported that humans have an immune system that more closely resembles that of the guinea pig in adjuvant-response features rather than the mouse system, which prevents the mouse results being extrapolated to human immunotherapy. Here we have constructed a tumor-implant system in guinea pigs to evaluate the antitumor potential of guinea pig IL-12 (gpIL-12) and guinea pig IL-18 (gpIL-18). Purified recombinant gpIL-12 and gpIL-18 were prepared and applied intraperitoneally to tumor-bearing (line 10 hepatoma) guinea pigs as the basis of the adjuvant immunotherapy. Intraperitoneal administration of gpIL-12 and gpIL-18 led to retardation of primary tumor growth and suppression of lymph-node metastasis in tumor-bearing guinea pigs. The permissible range of IL-12 appeared wider in guinea pigs than in mice. Even at an IL-12 dose higher than that in mice, there was no evidence of side-effects until day 26, when the guinea pigs were killed. gpIL-18 augmented the antitumor effect of gpIL-12 but exerted less ability to suppress lymph-node metastasis. The effects of gpIL-12 and gpIL-18 on the tumors implanted in guinea pigs will encourage us to use IL-12- and IL-18-inducible adjuvants for immunotherapy in human patients with solid cancer.