Immunoregulatory Effects Of Interleukin-12 In Chronic Hepatitis B Virus Infection

To investigate the immunoregulatory role of IL-I 2 for viral clearance in patients with chronic HBV infection, we studied the levels of PBMC IL-I 2 P40 mRNA and IL-12 P70 protein in patients with chronic hepatitis B, the asymptomatic chronic caniers and normal control. We also longitudinally studied PBMC IL-12 P70 protein in patients with chronic hepatitis B undergoing IFN-α treatment, that represents the process of HBV elimination in a condensed time frame. This allow a time course analysis of these immune reactions in relation to the exacerbation of hepatocyte lysis and viral clearance, manifested by the alanine aminotransferase (ALT) flare and HBeAg to anti-HBe seroconversion. IL-12P40 mRNA was detected by one step RT-PCR, IL-12 P70 protein was labeled with PE-conjugated and analyzed by flow cytometiy. The patients with active HBV replication showed a significantly higher of IL- 12 P40 mRNA and IL- 12 P70 in comparison with noninfected controls, while there was no difference in the expression of IL- 12 between the asymptomatic chronic carriers and controls. The high level of HBV DNA in serum was negatively correlated with those of IL-I 2 in PBMC. We found a trend that a high level of IL- 12 paralleled with a high grade of inflammatory activity and a rising of ALT. We longitudinally analyzed the levels of IL- 12 in patients with chronic hepatitis B. The pretreatment levels of IL-I 2 heterodimer were significantly higher among the responders to IFN-α in comparison with the nonresponders. The peak PBMC IL-12 levels in all patients who seroconverted to anti-HBe showed that above 2-fold above the corresponding pretreatment levels but not in nonresponders. The peak IL-12 levels in responders were significantly higher in comparison with those in nonresponders during the treatment. The present study indicates that, although immune-mediated hepatocyte lysis is a critical initial event in the process of viral clearance, a substantial increase in IL-I 2 production is required for a sustained immune control over HBV replication. The recombinant lL-12 may provide a specifically targeted immuno-therapy in chronic carriers with ongoing HBV replication.