Public Release Type:
Journal
Publication Year: 2013
Authors:
Lee WM,
Terrault N,
Khalili M,
Sterling RK,
Carithers RL,
Chang KM,
Feld JJ,
Keith J,
Kim WR,
Kowdley KV,
Lau D,
Levine DL,
Lok AS,
Park JJ,
Smith C,
Valiga ME,
Wahed AS,
Wong DK
Studies:
Hepatitis B Research Network
Participants with chronic hepatitis B (cHBV) are phenotypically classified as immune active (IA), immune tolerant (IT) or inactive carriers (IC) based on clinical parameters such as serum ALT and HBV DNA levels observed over time. These clinical cHBV phenotypes are relevant for therapeutic decision-making and prognosis. In this study, we investigated if specific immune effector and regulatory response patterns define pathogenetically relevant immune signatures for the cHBV phenotypes. Methods: 165 participants (46 HBeAg+ IA, 62 HBeAg- IA, 18 IT and 39 IC) were recruited for immune analyses between Feb 2011-Dec 2012 from 10 North American liver centers within the NIDDK-funded Hepatitis B Research Network. cHBV phenotypes were assigned based on historical data and compared to those based on HBeAg, HBV DNA and ALT values at the time of immune analysis. Antiviral T cell effector and regulatory responses were examined by proliferation and IFNγ/IL10 ELISPOT assays, with peripheral blood lymphocytes stimulated with overlapping peptides from HBV preS/S, pre-C/C and polymerase, plus Flu and PHA controls. Further immune regulatory and activation markers were examined by multi-color flow cytometry. Results: The 165 cHBV participants included 82% Asians and 48% females with median age 43 years, ALT 36 U/L, HBV DNA 4.9 log IU/L, and mostly HBV genotypes B (46%) or C (32%). Notably, historically-defined phenotypes differed from those based on lab values at the time of immune analysis in 34% of participants. As for antiviral T cell response, HBV-specific effector T cell proliferation and IFNγ responses as well as regulatory IL10 responses were generally suppressed with no clear distinction between the cHBV phenotypes. However, HBeAg+ IA participants had higher %FoxP3+ regulatory T cells (Tregs) than IT (p=0.0085) or IC participants (p=0.023), with a positive association between %CD8 T cells and serum ALT level (R=0.56, p=0.001). Moreover, HBeAg- IA participants tended to show greater inhibitory programmed death-1 (PD-1) receptor expression in CD8 T cells, suggesting an apparent differential induction of global immune regulatory pathways among cHBV phenotypes. Conclusions: cHBV is associated with weak circulating antiviral effector and IL10+ regulatory T cell responses regardless of clinical phenotypes. Interestingly, the immune active rather than tolerant phenotype was associated with FoxP3+ Tregs and PD-1 induction, suggesting compensatory induction of inhibitory pathways in immune active cHBV with potential pathogenetic and therapeutic relevance. Studies are ongoing to better define the immune signatures for cHBV phenotypes and their evolution in the HBRN.