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 investigated 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 administration, ribavirin did inhibit moderately the mitogen-stimulated mononuclear cell proliferation and growth of the CD4+ and CD8+ T cell subsets without apparent cytolysis. The ribavirin-IFN-alpha combination showed 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 modest increases in the T helper 1-like cytokine production by mononuclear cells. Higher ribavirin concentrations markedly inhibited IFN-gamma production, but augmented interleukins (IL) 2, 4, and 12 secretion. Conversely, 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 cause diverse effects on immunoregulatory cytokine secretion, and when combined, counteracted for production of IL-2 and IL-12, while upregulated mononuclear cell secretion of IFN-gamma and that of the anti-inflammatory cytokine IL-10. These findings suggest a non-cytolytic modulation of inflammatory responses induced by the drug combination, that may be relevant in the pathophysiology of chronic HCV infection.
Department of Hepatology, Fundación Jiménez Díaz, Madrid, Spain.
J
J
Martín
S
S
Navas
J A
JA
Quiroga
M
M
Pardo
V
V
Carreño
D015088:2',5'-Oligoadenylate Synthetase / Q000378:metabolism; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D004347:Drug Interactions; D004789:Enzyme Activation; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008875:Middle Aged; D012367:RNA, Viral / Q000378:metabolism; D011994:Recombinant Proteins; D012254:Ribavirin / Q000494:pharmacology*
D000998:Antiviral Agents; D016207:Cytokines; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D015088:2',5'-Oligoadenylate Synthetase