RESULTS.In AH patients and HBV-inoculated chimpanzees with HBsAg loss, CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 were elevated at hepatitis with subsequent decline of HBsAg. Interestingly, IL-21 elevation was observed only in resolving AH patients but not in nonresolvers. CXCL13 and IL-21 elevation was not observed in CH patients who failed to attain HBsAg loss, even at hepatic flare. A concomitant increase of CXCL13 and IL-21 was significant in CH patients who attained HBsAg seroconversion with a sequential therapy. CONCLUSION.Elevation of serum CXCL9, CXCL10, CXCL11, CXCL13, and IL-21 might be a hallmark of functional cure of AH or CH patients.

Indoleamine-2, 3-dioxygenase (IDO), an interferon-c-inducible enzyme catalyzing tryptophan into kynurenine, exerts dual functions in infectious diseases, acting as a suppressor of intracellular pathogens and as an immune regulator. We explored the roles of IDO in hepatitis B virus (HBV) clearance from infected patients. We examined IDO activity, serum chemokines, and cytokines in 53 HBV-positive patients (25 acute hepatitis, 14 chronic hepatitis, and 14 hepatic flare) and 14 healthy volunteers. In order to clarify the mechanisms of IDO induction and its impact on HBV replication, we used a culture model consisting of human natural killer cells, plasmacytoid dendritic cells, and HBV-transfected Huh7 cells in which IDO expression is controlled. A robust activation of IDO with an inverse correlation of alanine aminotransferase at the peak was observed in patients with acute hepatitis B but not in patients with hepatic flare. In acute hepatitis patients who eventually cleared HBV, IDO activity, chemokine (C-X-C motif ) ligand 9 (CXCL9), CXCL10, and CXCL11 increased at the peak of alanine aminotransferase. In contrast, in patients with hepatic flare, IDO activity remained at lower levels during the observation period, regardless of the surge of CXCL9, CXCL10, and CXCL11 at the alanine aminotransferase peak. Natural killer cells and plasmacytoid dendritic cells synergistically produced interferon-c and interferon-a, thereby enhancing IDO activity and HBV suppression in Huh7 cells. Such suppressor capacity of IDO on HBV was abrogated in IDO-knockout cells and recovered by the reinduction of IDO in the cells. Conclusion: IDO is an anti-HBV effector and an indicator of subsequent immune responses operative during the early phase of infection; its activity is boosted by coexisting natural killer cells and plasmacytoid dendritic cells. (HEPATOLOGY 2016;63:83-94) H epatitis B virus (HBV) is one of the most endemic pathogens in the world, the disease burden of which is approximately 350 million. Among them, 150 million patients are prone to progress to liver cirrhosis and hepatocellular carcinoma.1 To prevent or reduce the risk of hepatocarcinogenesis, it is desirable to eradicate HBV from chronically infected patients. The probability of spontaneous HBV eradication is <1% per year in patients with persistent HBV infection, even after the occurrence of severe hepatic flare (HF). 1 The difficulty is that even with extensive treatments using pegylated interferon-a (IFN-a) and/or lifelong nucleoside analogues (NAs), the clearance of hepatitis B surface antigen (HBsAg) as a surrogate for HBV eradication is less than 10%.2 Thus, the mechanisms of HBV eradication need to be explored for the development of novel treatment options for such hardto-cure populations.