Role of type 1 versus type 2 immune responses in liver during the onset of chronic woodchuck hepatitis virus infection

Immune response messenger RNAs (mRNA) were compared in liver during self‐limited (resolved) and chronic neonatal woodchuck hepatitis virus (WHV) infection. At week 14 postinfection (mid‐acute phase), mRNAs for leukocyte markers (CD3, CD4, CD8), type 1 cytokines and related transcription factors (IFN‐γ, TNF‐α, STAT4, T‐bet), and IL‐10 were increased in livers from resolving infections, but mRNAs of other type 1 (IL‐2) and type 2 (IL‐4, STAT6, and GATA3 markers remained at baseline levels. Increased coexpression of IFN‐γ and TNF‐α mRNAs correlated in most cases with lower levels of intrahepatic WHV covalently closed circular DNA (cccDNA). At the same time point postinfection, livers from woodchucks that eventually progressed to chronic infection had baseline or slightly elevated levels of CD and type 1 mRNAs, which were significantly lower (or elevated less frequently) compared with resolving woodchucks. Earlier, at week 8, there were no differences between the two outcome settings. During these early time points and at a later stage in chronic infection (15 months), type 2 mRNAs in carrier liver remained at baseline levels or, when elevated, were never in excess of those in resolving woodchucks. In conclusion, the onset and maintenance of neonatal chronic WHV infection are not associated with antagonistic type 2 immunoregulation of type 1 responses in liver. Accordingly, chronicity develops in association with a primary deficiency in the intrahepatic CD responses, especially involving CD8+ T lymphocytes, and in both extracellular (cytokine) and intracellular (transcriptional) type 1 response mediators. This has relevant implications for future treatment of chronic hepatitis B virus (HBV) infection in humans. (Hepatology 2003;37:771‐780.)

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