EFFECTS OF THE RIBAVIRIN INTERFERON-ALPHA COMBINATION ON CULTURED PERIPHERAL-BLOOD MONONUCLEAR-CELLS FROM CHRONIC HEPATITIS-C PATIENTS

The effects of ribavirin and interferon (IFN) alpha have been investig ated on cultured peripheral blood mononuclear cells, obtained from 15 patients with chronic hepatitis C virus (HCV) infection. At clinically relevant serum concentrations achieved during therapeutic administrat ion, ribavirin did inhibit moderately the mitogen-stimulated mononucle ar cell proliferation and growth of the CD4(+) and CD8(+) T cell subse ts without apparent cytolysis, The ribavirin-IFN-alpha combination sho wed activity against HCV with disappearance of HCV RNA in 27% of cases , and a synergy in the inducibility of the intracellular enzyme 2',5'- oligoadenylate synthetase, Such ribavirin concentrations induced modes t increases in the T helper 1-like cytokine production by mononuclear cells. Higher ribavirin concentrations markedly inhibited IFN-gamma pr oduction, but augmented interleukins (IL) 2, 4, and 12 secretion. Conv ersely, IFN-alpha tended to suppress IL 2, 4 and 12, but enhanced IFN- gamma and IL-10 secretion. Thus, ribavirin and IFN-alpha appear to cau se diverse effects on immunoregulatory cytokine secretion, and when co mbined, counteracted for production of IL-2 and IL-12, while upregulat ed mononuclear cell secretion of IFN-gamma and that of the anti-inflam matory cytokine IL-10, These findings suggest a non-cytolytic modulati on of inflammatory responses induced by the drug combination, that may be relevant in the pathophysiology of chronic HCV infection. (C) 1998 Academic Press.