Immune therapy for hepatoma by redox regulation of liver associated lymphocytes

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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