Eto Masatoshi, Koga Hirofumi, Noma Hideya, Yamaguchi Akito, Yoshikai Yasunobu, Naito Seiji
Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Urol Int. 2005;75(2):114-8. doi: 10.1159/000087163.
Intravesical immunotherapy with bacillus Calmette-Guérin (BCG) remains the most efficient modality for the treatment of carcinoma in situ and prevention of recurrences of Ta and T1 bladder tumors. Although elevations in a variety of urinary cytokines have been reported after BCG instillation, the mechanism by which BCG mediates antitumor activity has not been clearly established. Based upon our murine study, we reevaluated urinary cytokines before and after BCG instillations from the point of T helper (Th) 1/2 lymphocyte cytokine profiles.
Urinary interleukin (IL)-2, interferon (IFN)-gamma, IL-12, and IL-18 for Th1, and IL-4 for Th2 cytokines were measured by enzyme-linked immunosorbent assay just before and 4 h after the 4th or 5th instillation of 8 weekly instillations of 40-80 mg BCG, Tokyo strain, in 12 patients with superficial stages Ta and T1 bladder cancer, and carcinoma in situ.
Two representative Th1 cytokines, IL-2 and IFN-gamma, significantly increased in urine after intravesical BCG instillations. Interestingly, IL-12, a strong inducer of Th1 cytokines, did not increase in the urine after BCG instillations. Instead, IL-18, that has recently been reported to induce IFN-gamma production in T and NK cells in synergy with IL-12, obviously elevated in urine after BCG instillations. Urinary IL-4, a representative of Th2 cytokines, did not change at all after intravesical BCG instillations.
Our results clearly show the predominant importance of IL-18 followed by increases in Th1 cytokines, such as IL-2 and IFN-gamma, in the mechanisms of intravesical immunotherapy with BCG.
卡介苗（BCG）膀胱内免疫疗法仍然是治疗原位癌以及预防Ta和T1期膀胱肿瘤复发的最有效方法。尽管有报道称在BCG灌注后多种尿细胞因子水平会升高，但BCG介导抗肿瘤活性的机制尚未明确。基于我们的小鼠研究，我们从辅助性T（Th）1/2淋巴细胞细胞因子谱的角度重新评估了BCG灌注前后的尿细胞因子。
对12例Ta和T1期浅表性膀胱癌及原位癌患者，在每周8次、每次灌注40 - 80mg东京株BCG的第4次或第5次灌注前及灌注后4小时，通过酶联免疫吸附测定法检测尿中Th1细胞因子白细胞介素（IL）-2、干扰素（IFN）-γ、IL-12和IL-18，以及Th2细胞因子IL-4。
膀胱内灌注BCG后，两种代表性的Th1细胞因子IL-2和IFN-γ在尿中显著增加。有趣的是，Th1细胞因子的强诱导剂IL-12在BCG灌注后尿中并未增加。相反，最近报道与IL-12协同诱导T细胞和自然杀伤（NK）细胞产生IFN-γ的IL-18在BCG灌注后尿中明显升高。Th2细胞因子的代表尿IL-4在膀胱内灌注BCG后完全没有变化。
我们的结果清楚地表明，在BCG膀胱内免疫治疗机制中，IL-18起主要作用，随后是Th1细胞因子如IL-2和IFN-γ的增加。
