Interferon-gamma: biologic functions and HCV terapy (type I/II) (2 of 2 parts).
OBJECTIVE
To discuss exhaustively: 1) the interferon-gamma in inducing and modulating of immune responses; 2) impairment of IFN-gamma production that plays an important role in the persistence of infection, chronicity of inflammation, evolution in fibrosis; 3) in "vivo" effects of combination treatment with recombinant interferon-gamma and alpha in chronic HCV-infection.


METHODS
We reviewed the most important recent studios on relationship between IFN-gamma and chronic course of hepatitis C.


BACKGROUND
IFN-gamma is also a potent activator of macrophages. Exposure to IFN-gamma greatly enhances the microbicidal (and, to a lesser degree, citotoxic) activity of macrophages and induces them to secrete nitric oxide and monokines such as IL-1, IL-6, IL-8, and TFNalpha. It also activates neutrophils, NK cells, and vascular endothelial cells. Although IFN-gamma tends to promote the differentiation of B cells and CD8 T cells into immunologically active effectors, it does not promote lymphocyte proliferation. It enhances the activity of Thl cells, but inhibits the production of Th2 cells. IFN-gamma not only decreases the production of IL-4 by Th2 cells but also potently blocks the effects of IL-4 on B cells, promoting IgG1 production at the expense of IgE production. The inadequate Thl immunity as well as the weak HCV-specific T-cell response at the site of inflammation is associated with failure to clear the virus and a chronic course of disease. The production of IL-12 is critical for induction of Thl immunity, directed towards elimination of intracellular pathogenes and viruses. The core protein of HCV seems to have a suppressive action on IL-12 production at the transcriptional level. The specific Thl cell defect is correlated with insufficient Th and CTL responses, and lower production of type 1 cytokine (IL-2, IFN-gamma, lymphokine-activated killer cells). Taken together, these results are probably responsible for non-eradication of HCV infection. Particularly the effects of interferon-gamma may include inhibition of HCV virion production by an effect on viral RNA and protein synthesis, enhancement of immune lysis of HCV infected cells, inhibition of hepatic fibrosis by an effect on TGF-beta, and an effect on HCV induced carcinogenesis. These data suggest an HCV-related cellular immune defect in patients with hepatitis C that can be restored in most patients by IL-12.


CONCLUSIONS
The efficacy of IFN monotherapy in the HCV replicon system has been reported using IFN-alpha, IFN-gamma and IFN-beta. A recent clinical study to treatment chronic HCV involving sequential administration of IFN-alpha followed by IFN-gamma (IFN-alpha2b + IFN-gamma) showed a greater improvement over IFN monotherapy. This type of approach may lead to significant improvements in the therapeutic arsenal against chronic HCV infection.
Gattoni
A
A
F Magrassi Department of Clinical and Experimental Medicine, II University of Naples School of Medicine, Napoli, Italy.
Parlato
A
A
Vangieri
B
B
Bresciani
M
M
Derna
R
R
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001770:Blood Bactericidal Activity; D002986:Clinical Trials as Topic; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007371:Interferon-gamma / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology / Q000502:physiology / Q000627:therapeutic use*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism; D010587:Phagocytosis; D011994:Recombinant Proteins
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D009569:Nitric Oxide; D007371:Interferon-gamma