INTERLEUKIN-12 INDUCTION OF TH1 CYTOKINES IS IMPORTANT FOR VIRAL CLEARANCE IN CHRONIC HEPATITIS-B

Interleukin-12, a cytokine with an important role against intracellula r pathogens, promotes Th1 cell development, cell-mediated cytotoxicity , and interferon-gamma production. We investigated the immunoregulator y role of IL-12 in 72 chronic hepatitis B virus (HBV) carriers, 33 of whom were monitored longitudinally during interferon-alpha treatment. Serum levels of IL-12 heterodimer, IL-12 p40 subunit, IL-4, and Th1 cy tokines were determined by specific ELISAs, and hepatitis B core antig en-specific T cell response by a proliferation assay. Chronic HBV carr iers had higher serum levels of IL-12 and IL-12 p40 in comparison with controls (P < 0.01), suggesting that IL-12 production is not impaired . The longitudinal analysis revealed a further substantial increase (> 2.5 x baseline level) of bioactive IL-12 and Th1 cytokines in patient s who cleared HBV and seroconverted to anti-hepatitis B e, unlike the 23 nonresponders with persistent HBV replication (P < 0.01). The IL-12 peak followed the peak of hepatocytolysis by 9.8 +/- 2.8 wk and occur red either before or simultaneously with hepatitis B e seroconversion. Hepatitis B core antigen-specific T cell proliferation closely correl ated with hepatocytolysis and increased significantly in all patients (8 responders and 15 nonresponders) who developed hepatitis flare, irr espective of the virological outcome. These results provide in vivo ev idence that IL-12 may have an important role for viral clearance in ch ronic HBV infection.