Hihara J, Yamaguchi Y, Minami K, Noma K, Toge T
Department of Surgical Oncology, Hiroshima University, Japan.
Anticancer Res. 1999 Mar-Apr;19(2A):1077-84.
To determine the significance of interleukin (IL)-10 in antitumor immune response, the effect of the down-regulation of tumor-derived IL-10 on locoregional immunotherapy was investigated. C3H/HeN mice were intraperitoneally (i.p.) inoculated with IL-10-producing murine breast cancer cell line, FM3A, and treated with locoregional administration of OK-432 with or without anti-IL-10 monoclonal antibody (mAb). Anti-IL-10 mAb did not affect the in vitro growth of FM3A cells. Administration of OK-432 plus anti-IL-10 mAb remarkably delayed the retention of malignant ascites and prolonged the survival of mice compared with the administration of OK-432 alone. Spleen cells which were collected from mice treated with OK-432 plus anti-IL-10 mAb and further stimulated in vitro with inactivated FM3A cells exhibited significantly higher cytotoxicity against FM3A cells than those from mice treated with OK-432 alone or from the control mice. The expression of major histocompatibility complex (MHC) class II molecules on spleen cells was up-regulated in vitro by the addition of OK-432 and anti-IL-10 mAb. Using semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR), cytokine mRNA levels of peritoneal exudate cells (PEC) and spleen cells were assessed on day 7 (before treatment) and day 14 (after treatment). In PEC, increased expression of IL-2 was observed with the administration of OK-432 plus anti-IL-10 mAb. In spleen cells, the expression of IL-2, IL-12 and IFN-gamma were strongly induced, and IL-4 expression was reduced by the administration of OK-432 plus anti-IL-10 mAb. It is suggested that down-regulation of tumor-derived IL-10 induces the up-regulation of the T helper type (Th) 1 population, resulting in an enhancement of the efficacy of locoregional immunotherapy with OK-432.
为了确定白细胞介素（IL）-10在抗肿瘤免疫反应中的意义，研究了肿瘤源性IL-10下调对局部区域免疫治疗的影响。将产生IL-10的小鼠乳腺癌细胞系FM3A腹腔内（i.p.）接种到C3H/HeN小鼠体内，并在有或没有抗IL-10单克隆抗体（mAb）的情况下，对其进行局部区域注射OK-432治疗。抗IL-10 mAb不影响FM3A细胞的体外生长。与单独注射OK-432相比，联合注射OK-432和抗IL-10 mAb显著延迟了恶性腹水的潴留，并延长了小鼠的生存期。从接受OK-432加抗IL-10 mAb治疗的小鼠中收集的脾细胞，在体外经灭活的FM3A细胞进一步刺激后，对FM3A细胞的细胞毒性显著高于单独接受OK-432治疗的小鼠或对照小鼠的脾细胞。通过添加OK-432和抗IL-10 mAb，体外上调了脾细胞上主要组织相容性复合体（MHC）II类分子的表达。使用半定量逆转录-聚合酶链反应（RT-PCR），在第7天（治疗前）和第14天（治疗后）评估腹腔渗出细胞（PEC）和脾细胞的细胞因子mRNA水平。在PEC中，联合注射OK-432和抗IL-10 mAb后观察到IL-2表达增加。在脾细胞中，联合注射OK-432和抗IL-10 mAb强烈诱导了IL-2、IL-12和IFN-γ的表达，并降低了IL-4的表达。提示肿瘤源性IL-10的下调诱导了辅助性T细胞1型（Th1）群体的上调，从而增强了OK-432局部区域免疫治疗的疗效。
