Immune therapy for hepatoma by redox regulation of liver associated lymphocytes

氧化还原过程涉及多种生物过程，包括信号转导、基因表达和细胞增殖，一些分子已被确定为细胞激活中的氧化还原调节因子。肝硬变患者血清和外周血单个核细胞中的谷胱甘肽水平低于健康人，如免疫缺陷，如艾滋病。在本研究中，我们评估了谷胱甘肽在调节淋巴细胞，特别是肝脏相关淋巴细胞功能方面的意义，并提出了一种利用氧化还原调节剂进行肝肿瘤免疫治疗的新策略。用N-乙酰-L-半胱氨酸(NAC)培养大鼠肝单核细胞，可恢复肝硬变大鼠肝单核细胞受抑制的杀伤活性和细胞内谷胱甘肽含量，但对正常肝脏NK活性介导的单核细胞活性无影响。这一发现进一步…More支持细胞内有足够的谷胱甘肽(GSH)对肝脏MNC的最佳NK活性的要求，并提出了一种生理机制，即谷胱甘肽的减少可能与肝硬变个体肝癌的增加和肝硬变动物肝癌细胞的生长增加有关。因此，GSH对肝脏免疫的最佳功能是重要的，从而防止肝癌的发展。为了研究免疫疗法激活肝细胞癌患者肝MNC的可能性，我们接下来评估了肝细胞癌患者的肝MNC和PBMNC的细胞毒性。研究了通过细胞因子激活这些细胞的策略，并通过依赖氧化还原的过程来调节这种激活。肝细胞癌患者外周血单个核细胞的细胞毒作用明显低于对照组，而肝细胞癌患者外周血单个核细胞的细胞毒作用与对照组相比无明显变化。接下来，我们测量了细胞内GSH，这被认为是白细胞介素2(IL-2)增强细胞毒性所必需的。肝细胞癌患者肝单个核细胞内谷胱甘肽水平明显低于对照组。体外给予NAG不仅能恢复细胞内GSH水平，而且能增强IL-2刺激的肝细胞对肝癌MNC的细胞毒作用。提示肝MNC肝癌细胞内GSH在体外可调节肝MNC的细胞毒作用，NAG可作为肝细胞癌免疫治疗的辅助手段。较少

Redox processes have been implicated in various biologic processes, including signal transduction, gene expression, and cell proliferation, and several molecules have been identified as redox regulators in cell activation. Glutathione levels in serum and peripheral blood mononuclear cells of cirrhosis patients are lower compared to values detected in healthy individuals, like immunodeficiencies, such as AIDS.In this study, we evaluate the significance of glutathione in regulating the functions of lymphocytes, especially those of liver-associated lymphocytes (liver MNC), and propose a novel strategy for immune therapy of liver neoplasms with the use of redox-modulating agents. We observed that the administration of N-acetyl-L-cysteine (NAC) to the culture of rat liver MNC restored both suppressed killing activity and the intracellular glutathione contents of liver MNC in the cirrhotic rat livers, while having no effect on NK activity mediated MNC from normal livers. This finding further … More supports the requirement of adequate intracellular glutathione (GSH) for optimal NK activity by liver MNC, and suggests a physiological mechanism, i.e., decreased glutathione, may be causally associated with the increased of hepatoma in cirrhotic individuals and the increased growth of hepatoma cells in cirrhotic animals. Thus, GSH is important to the optimal functioning of hepatic immunity that protects against hepatoma development.To examine the possibility of immunotherapy for activating liver MNC in hepatocellular carcinoma, we next evaluated the cytotoxicity of liver MNC and PBMNC in hepatocellular carcinoma patients. Strategies to activate these cells by cytokines, and to regulate such activation by redox-dependent processes were examined. Cytotoxicity of liver MNC but not PBMNC in hepatocellular carcinoma patients were significantly decreased compared with those of controls, despite no alteration in the subpopulation of liver MNC between the two groups. We next measured intracellular GSH which is thought to be required for the enhancement of the cytotoxicity by interleukin-2 (IL-2). Intracellular glutathione levels of liver MNC in hepatocellular carcinoma were significantly lower than that of controls. In vitro administration of NAG not only restored intracellular GSH levels, but also enhanced the IL-2-stimulated cytotoxicity of liver MNC in hepatocellular carcinoma. These observations indicate that intracellular GSH of liver MNC hepatocellular carcinoma may modulate the cytotoxicity of liver MNC in vitro, and that NAG may be effective as an adjunct to immunotherapy for hepatocellular carcinoma. Less