Department of Urology, University of Iowa, Iowa City, Iowa 52242, USA.
J Urol. 2012 Jun;187(6):2228-35. doi: 10.1016/j.juro.2012.01.030. Epub 2012 Apr 13.
Proper induction of the T-helper type 1 immune response is required for effective bacillus Calmette-Guérin immunotherapy for bladder cancer. Interleukin-10 down-regulates the T-helper 1 response and is associated with bacillus Calmette-Guérin failure. We investigated whether blocking interleukin-10 receptor 1 would enhance the bacillus Calmette-Guérin induced T-helper type 1 immune response and anti-bladder cancer immunity in a mouse model.
Splenocytes were incubated with bacillus Calmette-Guérin or bacillus Calmette-Guérin plus control IgG1, anti-interleukin-10 receptor 1 mAb or anti-interleukin-10 neutralizing mAb, followed by enzyme-linked immunosorbent assay of interferon-γ production. Bladder RNA was extracted after intravesical bacillus Calmette-Guérin plus intraperitoneal IgG1 or anti-interleukin-10 receptor 1 mAb and analyzed by reverse transcriptase and/or quantitative polymerase chain reaction. Urine was collected and analyzed by enzyme-linked immunosorbent assay. Mice bearing a luciferase expressing MB49 orthotopic tumor were treated with intravesical bacillus Calmette-Guérin plus intraperitoneal IgG1 or anti-interleukin-10 receptor 1 mAb. Tumor response was assessed by bioluminescent imaging and bladder weight measurement.
Bacillus Calmette-Guérin plus anti-interleukin-10R1 mAb induced significantly higher interferon-γ production by splenocytes than bacillus Calmette-Guérin plus anti-interleukin-10 mAb. Bacillus Calmette-Guérin plus anti-interleukin-10 receptor 1 mAb also induced significantly higher interferon-γ mRNA and protein in bladder and urine, respectively, in a dose dependent manner. Treatment with phosphate buffered saline, bacillus Calmette-Guérin plus control IgG1 and bacillus Calmette-Guérin plus anti-interleukin-10 receptor 1 mAb showed a 0% tumor-free rate with a 20% death rate, a 20% tumor-free rate with a 20% death rate and a 40% tumor-free rate with a 0% death rate, respectively. Bladder weight also revealed the effect of anti-interleukin-10 receptor 1 mAb on the bacillus Calmette-Guérin induced bladder tumor response.
Anti-interleukin-10 receptor 1 mAb enhanced the bacillus Calmette-Guérin induced T-helper type 1 immune response and anti-bladder cancer immunity. A humanized form of this mAb warrants future investigation for bacillus Calmette-Guérin treatment of bladder cancer.
辅助性 T 细胞 1 型免疫反应的正确诱导是卡介苗免疫疗法治疗膀胱癌的有效手段。白细胞介素-10 下调 T 辅助 1 反应，并与卡介苗失败有关。我们研究了在小鼠模型中阻断白细胞介素-10 受体 1 是否会增强卡介苗诱导的 T 辅助 1 型免疫反应和抗膀胱癌免疫。
将脾细胞与卡介苗或卡介苗加对照 IgG1、抗白细胞介素-10 受体 1 mAb 或抗白细胞介素-10 中和 mAb 孵育，然后通过酶联免疫吸附试验检测干扰素-γ的产生。用卡介苗加腹腔内 IgG1 或抗白细胞介素-10 受体 1 mAb 处理膀胱后提取膀胱 RNA，并通过逆转录和/或定量聚合酶链反应进行分析。收集尿液并通过酶联免疫吸附试验进行分析。用表达荧光素酶的 MB49 原位肿瘤的小鼠进行治疗，用卡介苗加腹腔内 IgG1 或抗白细胞介素-10 受体 1 mAb。通过生物发光成像和膀胱重量测量评估肿瘤反应。
卡介苗加抗白细胞介素-10R1 mAb 诱导的脾细胞干扰素-γ产生明显高于卡介苗加抗白细胞介素-10 mAb。卡介苗加抗白细胞介素-10 受体 1 mAb 也以剂量依赖的方式在膀胱和尿液中分别诱导干扰素-γ mRNA 和蛋白的产生。用磷酸盐缓冲盐水、卡介苗加对照 IgG1 和卡介苗加抗白细胞介素-10 受体 1 mAb 处理，肿瘤无进展率分别为 0%、20%死亡率，肿瘤无进展率分别为 20%、20%死亡率和 40%、0%死亡率。膀胱重量也显示了抗白细胞介素-10 受体 1 mAb 对卡介苗诱导的膀胱肿瘤反应的影响。
抗白细胞介素-10 受体 1 mAb 增强了卡介苗诱导的 T 辅助 1 型免疫反应和抗膀胱癌免疫。这种 mAb 的人源化形式值得进一步研究，以用于卡介苗治疗膀胱癌。
