Impact of Alpha Interferon and Ribavirin on the Function of Maturing Dendritic Cells

Abstract

Alpha interferon and ribavirin are required in combination to achieve a sustained virological response in the treatment of hepatitis C virus (HCV) infection. Alpha interferon has direct antiviral activity and also enhances HCV-specific T-cell responses. Ribavirin has little direct activity against HCV but reduces hepatic inflammation. It is therefore likely that these drugs in combination have hitherto unidentified immunological effects. In the present study we investigated the effects of alpha interferon and ribavirin on dendritic cell (DC) maturation and cytokine production induced by double-stranded RNA in vitro. Alpha interferon alone enhanced the expression of HLA class I, HLA class II, and CD86 on immature DCs but did not stimulate full DC maturation, which requires the expression of CD83. Alpha interferon enhanced the production of interleukin 12 p70 [IL-12(p70)] and tumor necrosis factor alpha (TNF-␣) but had no effect on IL-10 production. In contrast, ribavirin at physiological doses had no effect on DC maturation but markedly suppressed the production of TNF-␣, IL-10, and IL-12(p70). The suppression of cytokines by ribavirin cannot be explained by the induction of DC apoptosis or cell death. Quantitative PCR confirmed that cytokine suppression occurs at the level of mRNA. The suppression of IL-12(p70) and TNF-␣ in maturing DCs may explain the reduction in hepatic inflammation observed during ribavirin monotherapy. Combination alpha interferon-ribavirin therapy may alter the cytokine profile of maturing DCs overall by suppressing IL-10 production but maintaining IL-12(p70) and TNF-␣ production, a pattern that would favor viral elimination through downstream effects on T cells.Hepatitis C virus (HCV) infection is a global public health problem and a significant cause of patient morbidity and mortality (14). Alpha interferon (IFN-␣) in combination with ribavirin (1-␤-D-ribofuranosyl-1H-1,2,4-triazole-3 carboxamide) is now the mainstay of treatment of HCV infection and leads to sustained viral eradication in 46 to 76% of infected patients, depending on the HCV genotype (13). The mechanisms of action of these drugs are poorly understood. IFN-␣ monotherapy leads to sustained viral eradication in only 8% of infected patients (28), while ribavirin monotherapy has a minimal effect on the viral load but significantly reduces hepatic inflammation (11,15,29). Clearly, then, these drugs have effects, hitherto unidentified, which in combination promote HCV control.During persistent HCV infection, HCV-specific T-cell responses are weak and very difficult to detect ex vivo (19). However, these responses are enhanced during combination therapy (6), and the HCV-specific lymphoproliferative capacity has been associated with a sustained virological response to therapy (9). Furthermore, the enhanced virological response rates seen with pegylated IFN-␣ for the treatment of HCV have been attributed to sustained HCV-specific CD4ϩ -T-cell responses (16). These studies clearly support the hypothesis that long-term viral control...

Interleukin-12: An Update on its Immunological Activities, Signaling and Regulation of Gene Expression

“…The IL-12-enhancing effect of IFN-α on DCs was corroborated in an independent study where doublestranded RNA was used to induce DC maturation and cytokine production. IFN-α enhanced the production of IL-12 and TNF-α induced by double-stranded RNA but had no effect on IL-10 production [140].…”

Preferential loss of IL‐2–secreting CD4+ T helper cells in chronic HCV infection†

“…This was because we were interested in testing patients who had not been previously treated, because IFN-␣ and ribavirin can influence T cell function and also cytokine secretion profiles. 22,36 Additionally, we did not assess the relationship between IL-2 secretion and viral load. A prospective study aiming to look at the IL-2 secretion in more severely affected patients over a range of viral loads is underway, as well as assessing the potential impact of therapy.…”

Altered chemotactic response of myeloid and plasmacytoid dendritic cells from patients with chronic hepatitis C: role of alpha interferon

“…IFN-a is typically used in combination with RBV for treatment of chronic HCV infection (Stark et al, 1998). RBV at physiological doses has no effect on MDC phenotype, whereas IFN-a has been shown consistently to induce MDC maturation (Barnes et al, 2004;Luft et al, 1998). Our results indicated that IFN-a-exposed MDCs from HCV patients acquired a mature phenotype, as defined by the upregulation of HLA-DR and of costimulatory and adhesion molecules, as well as of the maturation marker CD83.…”