Immune therapy for hepatoma by redox regulation of liver associated lymphocytes

氧化还原过程涉及各种生物过程，包括信号转导、基因表达和细胞增殖，并且已经鉴定了几种分子作为细胞活化中的氧化还原调节剂。肝硬化患者的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。在这项研究中，我们评估谷胱甘肽在调节淋巴细胞，特别是肝相关淋巴细胞功能中的意义（肝MNC），并提出了一种新的策略，肝肿瘤的免疫治疗与氧化还原调节剂的使用。我们观察到，N-乙酰-L-半胱氨酸（NAC）对大鼠肝MNC的培养，既恢复了被抑制的杀伤活性，又恢复了肝MNC细胞内谷胱甘肽含量，而对正常肝MNC介导的NK活性没有影响。这一发现进一步 ...更多信息 支持肝脏MNC需要足够的细胞内谷胱甘肽（GSH）来获得最佳NK活性，并提出了一种生理机制，即，谷胱甘肽的减少可能与肝癌患者肝癌的增加和肝癌动物肝癌细胞的生长增加有关。因此，GSH是重要的肝脏免疫的最佳功能，防止肝癌development.To检查免疫治疗的可能性，激活肝细胞癌中的肝MNC，我们接下来评估肝细胞癌患者的肝MNC和PBMNC的细胞毒性。研究了通过细胞因子激活这些细胞以及通过氧化还原依赖性过程调节这种激活的策略。与对照组相比，肝癌患者的肝MNC的细胞毒性显著降低，但PBMNC的细胞毒性没有显著降低，尽管两组之间的肝MNC亚群没有改变。我们接下来测量细胞内GSH，其被认为是增强白细胞介素-2（IL-2）的细胞毒性所需的。肝癌患者肝MNC细胞内谷胱甘肽水平明显低于对照组。在体外给予NAG不仅恢复细胞内GSH水平，但也增强了IL-2刺激的肝细胞癌的肝MNC的细胞毒性。这些观察结果表明，肝MNC肝癌细胞内的GSH可以调节肝MNC在体外的细胞毒性，NAG可能是有效的作为辅助免疫治疗肝癌。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