Novel insights into the mechanism of action of intravesical immunomodulators.
Novel insights into the mechanism of action of intravesical immunomodulators.
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对膀胱内免疫调节剂作用机制的新见解。
作者：
D. Mitropoulos
到目前为止，膀胱内免疫调节剂的确切作用机制仍不清楚。在体外，干扰素α直接作用于肿瘤细胞，在诱导其分化的同时抑制其增殖。尿路上皮细胞和移行细胞癌(TCC)细胞表达干扰素-α受体，其表达密度与病变级别有关。干扰素-α可能通过抑制环氧合酶-1的作用，减少肿瘤切除(TUR)后肿瘤附近正常尿路上皮的新生微血管密度。此外，干扰素-α诱导肿瘤相关抗原和MHC抗原的膜表达，为细胞免疫反应提供基础。在膀胱内给药时，干扰素-α可能导致局部和全身T细胞和NK细胞的激活。通过监测尿液中一氧化氮(NO)终末产物和免疫组织化学方法检测诱导型一氧化氮合酶(INOS)的表达，我们发现干扰素-α可诱导尿路上皮iNOS表达，进而形成过氧亚硝酸盐，这可能是干扰素-α抗肿瘤作用的机制之一。卡介苗(BCG)被认为通过细菌抗原85复合体和纤维连接蛋白相互作用而与膀胱壁结合。虽然已经报道了全身反应(细胞免疫反应的进化、全身细胞因子和氧自由基的产生)，但可能的情况是，暴露于卡介苗会导致大量的局部免疫反应，其特征是诱导细胞因子在尿液和膀胱壁中的表达，以及粒细胞和单核细胞对膀胱壁的显著渗透。卡介苗诱导的肿瘤细胞表型变化使其既能作为淋巴因子激活的杀伤细胞靶标，又能作为抗原提呈细胞。虽然卡介苗可以直接作用于肿瘤细胞的增殖，但辅助性和细胞毒性T细胞，以及很可能是NK细胞，对于任何抗肿瘤作用都是绝对必要的。肿瘤细胞的杀伤是通过FasL、穿孔素和肿瘤坏死因子-α介导的。在最近的一项研究中，我们发现卡介苗在体内上调了正常人尿路上皮中iNOS的表达，提示NO在卡介苗介导的抗肿瘤活性中发挥了作用。
To date, the precise mechanism of intravesical immunomodulators remains unknown. In vitro, interferon alpha (IFN-alpha) acts directly on neoplastic cells and inhibits their proliferation while it induces their differentiation. Urothelium and transitional cell carcinoma (TCC) cells express IFN-alpha receptor, the density of which correlates with lesion grade. IFN-alpha reduces neo-microvascular density in the normal urothelium adjacent to the tumor after transurethial resection (TUR), possibly via inhibition of COX-1. Moreover, IFN-alpha induces the membrane expression of tumor-related antigens and MHC antigens, providing a basis for a cellular immune response. When given intravesically, IFN-alpha may result in local and systemic T cell and NK cell activation. By monitoring nitric oxide (NO) end-products in urine and evaluating inducible nitric oxide synthase (iNOS) expression immunohistochemically, we were able to show that IFN-alpha may induce urothelial iNOS expression with subsequent formation of peroxynitrite, which might contribute to the antineoplastic action of IFN-alpha. Bacillus Calmette-Guerin (BCG) is thought to bind to the bladder wall via interaction between the bacterial antigen 85 complex and fibronectin. Although systemic reactions (evolution of cellular immune response, systemic production of cytokines and oxygen free radicals) have been reported, a likely scenario is that exposure to BCG results in a massive local immune response, characterized by induced expression of cytokines in the urine and in the bladder wall, and by a marked infiltration of the bladder wall by granulocytes and mononuclear cells. BCG-induced changes in tumor cell phenotype render them able to act both as lymphokine-alphactivated killer cell targets and antigen presenting cells. Although BCG may act directly on the proliferation of tumor cells, helper and cytotoxic T cells and, most probably, NK cells are absolutely necessary for any antitumor effects. Tumor cell killing is mediated through FasLigand, perforin and TNF-alpha. In a recent study, we found that BCG up-regulated iNOS expression in normal human urothelium in vivo, suggesting a role for NO in BCG-mediated antitumor activity.
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膀胱内卡介苗治疗膀胱癌期间产生白细胞介素 2。
DOI：
10.1016/0090-1229(86)90043-7
发表时间：
1986
期刊：
Clinical immunology and immunopathology
影响因子：
--
作者：
Ratliff,TL;Haaff,EO;Catalona,WJ
通讯作者：
Catalona,WJ
DOI：
10.1016/s0022-5347(01)67292-6
发表时间：
1995-07
期刊：
The Journal of urology
影响因子：
--
作者：
M. M. Shemtov-M.;D. L. Cheng;L. Kong;W. Shu;M. Sassaroli;M. Droller;B. Liu
通讯作者：
M. M. Shemtov-M.;D. L. Cheng;L. Kong;W. Shu;M. Sassaroli;M. Droller;B. Liu
DOI：
10.1006/niox.1998.0169
发表时间：
1998-02
期刊：
Nitric oxide : biology and chemistry
影响因子：
--
作者：
W. Samlowski;Chang-Yeol Yim;J. Mcgregor
通讯作者：
W. Samlowski;Chang-Yeol Yim;J. Mcgregor
膀胱癌患者免疫治疗期间对卡介苗的抗体反应。
影响因子：
11.2
作者：
Winters,WD;Lamm,DL
通讯作者：
Lamm,DL
卡介苗与纤连蛋白的羧基末端肝素结合域相互作用：对 BCG 介导的抗肿瘤活性的影响。
DOI：
10.1016/s0022-5347(17)32567-3
发表时间：
1994
期刊：
The Journal of urology
影响因子：
--
作者：
Cheng,DL;Shu,WP;Choi,JC;Margolis,EJ;Droller,MJ;Liu,BC
通讯作者：
Liu,BC