Mitropoulos Dionisios N
1st Department of Urology, Athens Medical School, Athens, Greece.
In Vivo. 2005 May-Jun;19(3):611-21.
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.
迄今为止，膀胱内免疫调节剂的确切作用机制尚不清楚。在体外，α干扰素（IFN-α）直接作用于肿瘤细胞，抑制其增殖并诱导其分化。尿路上皮和移行细胞癌（TCC）细胞表达IFN-α受体，其密度与病变分级相关。经尿道切除术（TUR）后，IFN-α可能通过抑制COX-1降低肿瘤旁正常尿路上皮中的新生微血管密度。此外，IFN-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了基础。膀胱内给予IFN-α可能导致局部和全身T细胞及NK细胞激活。通过监测尿液中的一氧化氮（NO）终产物并免疫组化评估诱导型一氧化氮合酶（iNOS）的表达，我们能够证明IFN-α可能诱导尿路上皮iNOS表达，随后形成过氧亚硝酸盐，这可能有助于IFN-α的抗肿瘤作用。卡介苗（BCG）被认为通过细菌抗原85复合物与纤连蛋白之间的相互作用与膀胱壁结合。虽然已有全身反应（细胞免疫反应的演变、细胞因子和氧自由基的全身产生）的报道，但一种可能的情况是，接触BCG会导致大量局部免疫反应，其特征是尿液和膀胱壁中细胞因子的诱导表达，以及粒细胞和单核细胞对膀胱壁的显著浸润。BCG诱导的肿瘤细胞表型变化使其能够同时作为淋巴因子激活的杀伤细胞靶标和抗原呈递细胞。虽然BCG可能直接作用于肿瘤细胞的增殖，但辅助性T细胞和细胞毒性T细胞以及极有可能的NK细胞对于任何抗肿瘤作用都是绝对必要的。肿瘤细胞杀伤是通过Fas配体、穿孔素和TNF-α介导的。在最近的一项研究中，我们发现BCG在体内上调了正常人尿路上皮中iNOS的表达，提示NO在BCG介导的抗肿瘤活性中发挥作用。
