A Role for B Cells to Transmit Hepatitis C Virus Infection.

Hepatitis C virus (HCV) is highly variable and transmits through infected blood to establish a chronic liver infection in the majority of patients. Our knowledge on the infectivity of clinical HCV strains is hampered by the lack of in vitro cell culture systems that support efficient viral replication. We and others have reported that HCV can associate with and infect immune cells and may thereby evade host immune surveillance and elimination. To evaluate whether B cells play a role in HCV transmission, we assessed the ability of B cells and sera from recent (<2 years) or chronic (≥ 2 years) HCV patients to infect humanized liver chimeric mice. HCV was transmitted by B cells from chronic infected patients whereas the sera were non-infectious. In contrast, B cells from recently infected patients failed to transmit HCV to the mice, whereas all serum samples were infectious. We observed an association between circulating anti-glycoprotein E1E2 antibodies and B cell HCV transmission. Taken together, our studies provide evidence for HCV transmission by B cells, findings that have clinical implications for prophylactic and therapeutic antibody-based vaccine design.

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.

Multifocal inflammatory pseudotumor of the liver: dynamic gadolinium-enhanced, ferumoxides-enhanced, and mangafodipir trisodium-enhanced MR imaging findings.

The MRI characteristics of a multifocal inflammatory pseudotumor of the liver are described. Emphasis is placed on the appearances following intravenous administration of both non-specific and liver-specific MR contrast agents. On post-gadolinium gradient-echo (GE) images an early, intense, and peripheral enhancement was followed by a homogeneous, complete, and persistent enhancement. Lesions showed no uptake following administration of ferumoxides particles nor mangafodipir trisodium, respectively. During follow-up, a peripheral hyperintense rim appeared on precontrast T1-weighted images, a feature not previously described.

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.