Impaired ability of interferon-alpha-primed dendritic cells to stimulate Th1-type CD4 T-cell response in chronic hepatitis C virus infection.
In interferon-alpha (IFN-alpha)/ribavirin combination therapy for chronic hepatitis C (CHC), an enhanced T helper 1 (Th1) response is essential for the eradication of hepatitis C virus (HCV). We aimed to elucidate the role of IFN-alpha or IFN-alpha/ribavirin in dendritic cell (DC) ability to induce Th1 response in HCV infection. We generated monocyte-derived DC from 20 CHC patients and 15 normal subjects driven by granulocyte-macrophage colony-stimulating factor and interleukin 4 (IL-4) without IFN-alpha (GM/4-DC), with IFN-alpha (IFN-DC), with ribavirin (R-DC) or with IFN-alpha/ribavirin (IFN/R-DC) and compared their phenotypes and functions between the groups. We also compared them in 14 CHC patients between who subsequently attained sustained virological response (SVR) and who did not (non-SVR) by 24 weeks of IFN-alpha/ribavirin therapy. Compared with GM/4-DC, IFN-DC displayed higher CD86 expression, but lesser ability to secrete IL-10 and were more potent to prime CD4(+) T cells to secrete IFN-gamma and IL-2. Such differences were more significant in healthy subjects than in CHC patients. No additive effect of ribavirin was observed in DC phenotypes and functions in vitro either which was used alone or in combined with IFN-alpha. However, in the SVR patients, an ability of IFN/R-DC to prime T cells to secrete IFN-gamma and IL-2 was higher than those of IFN-DC and those of IFN/R-DC in the non-SVR group, respectively. In conclusion, DC from CHC patients are impaired in the ability to drive Th1 in response to IFN-alpha. Such DC impairment is restored in vitro by the addition of ribavirin in not all but some patients who cleared HCV by the combination therapy.
Miyatake
H
H
Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita-shi, Osaka, Japan.
Kanto
T
T
Inoue
M
M
Sakakibara
M
M
Kaimori
A
A
Yakushijin
T
T
Itose
I
I
Miyazaki
M
M
Kuzushita
N
N
Hiramatsu
N
N
Takehara
T
T
Kasahara
A
A
Hayashi
N
N
D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology*; D051940:B7-2 Antigen / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D012254:Ribavirin / Q000494:pharmacology; D019562:Viral Load
D000998:Antiviral Agents; D051940:B7-2 Antigen; D016898:Interferon-alpha; D007376:Interleukin-2; D016753:Interleukin-10; D012254:Ribavirin; D007371:Interferon-gamma