Evolution of hepatitis C virus-specific T cell responses and cytokine production in chronic hepatitis C patients treated with high doses of interferon-alpha.
OBJECTIVE
To assess the evolution of in vitro T cell response to hepatitis C virus (HCV) Core, E1, E2 and NS3 antigens in 10 patients with chronic hepatitis C, before, during and after a high dose interferon alpha (IFN-alpha) therapy, and to evaluate the influence of IFN-alpha on the in vivo and in vitro production of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma).


METHODS
T cell response to HCV antigens was evaluated by lymphoproliferation assays. In vivo and in vitro cytokine production was evaluated at weeks 0, 4, 8, and 12 of IFN-alpha therapy by enzyme immunoassays.


RESULTS
In general, of all HCV antigens tested throughout the follow-up, those belonging to the Core region were the most immunostiumlatory. This observation was valid in IFN-alpha responders as well as IFN-alpha non-responders. The lymphoproliferative response to HCV antigens increased during IFN-alpha therapy. Serum levels of TNF-alpha were significantly increased in HCV patients, and six out of ten patients showed increased IFN-gamma serum levels. A significant decrease of IFN-gamma levels was observed during therapy and the same trend was seen for TNF-alpha. Mitogen-stimulated TNF-alpha and IFN-gamma production before therapy did not differ from that of normal controls, however, the cytokine production was reduced at week 4 of therapy, corresponding with a clinical improvement. A return to pretreatment values was observed after 8 weeks of therapy.


CONCLUSIONS
a) Core antigens are the most immunostimulatory HCV antigens at the T cell level in chronic hepatitis C patients; b) High dose IFN-alpha therapy induces an increase in lymphoproliferative response to HCV antigens; c) Serum levels of TNF-alpha are increased in HCV patients; d) High dose IFN-alpha therapy induces a decrease in serum levels of IFN-gamma; e) High dose IFN-alpha therapy induces a transiently decreased mitogen-induced TNF-alpha and IFN-gamma production.
Alvarado Esquivel
Cosme
C
Departamento de Inmunología y Biología Molecular, Instituto de Investigación Científica, Departamento de Microbiología, Facultad de Medicina, UJED. alvaradocosme@yahoo.com
Elewaut
André
A
Philippé
Jan
J
Elewaut
Ann E
AE
Desombere
Isabelle
I
Maertens
Geert
G
Leroux-Roels
Geert
G
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002478:Cells, Cultured; D003470:Culture Media; D005260:Female; D018936:Hepatitis C Antigens / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology* / Q000627:therapeutic use; D016898:Interferon-alpha / Q000494:pharmacology* / Q000627:therapeutic use; D007371:Interferon-gamma / Q000096:biosynthesis*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D013601:T-Lymphocytes / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D014758:Viral Core Proteins
D000998:Antiviral Agents; D003470:Culture Media; D018936:Hepatitis C Antigens; D007155:Immunologic Factors; D016898:Interferon-alpha; D014409:Tumor Necrosis Factor-alpha; D014758:Viral Core Proteins; D007371:Interferon-gamma