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559
Overcoming Liver Tolerance to Clear Persistent
HBV Infection
Anna Kosinska1, Anna Kallin2, Ulrike Protzer1 and Percy
Knolle2, (1)Institute of Virology, Technical University
/ Helmholtz Center Munich, (2)Institute of Molecular
Immunology, University Hospital Rechts Der Isar Technical
University of Munich
Background: The liver harbors unique immunological
functions in both, immunity and tolerance. Particularly,
induction of immune tolerance through dedicated local
antigen-presenting cells in the liver in combination with the
unique hepatic microenvironment is held responsible for
development of persistent hepatitis virus infection (Knolle,
Maini & Protzer Nat Rev Immunol 2012). We have recently
reported that the tolerogenic liver function can be overcome by
pharmacological induction through TLR ligands of intrahepatic
myeloid cell aggregates, that we termed iMATEs. iMATEs
form cocoon-like structures that enforce very strong local
expansion of anti-viral effector CD8 T cells in the liver (Huang
et al Nat Immunol 2013). Methods: AAV-HBV transduction of
hepatocytes in immune competent mice, protein prime- MVAboost
therapeutic hepatitis B vaccination, characterization of
HBV-specific immunity, viral parameters and clearance of HBVinfected
hepatocytes from the liver Results: Here, we present
new insight into the mechanisms how iMATEs overcome local
regulatory cues in the liver and how iMATEs can be employed
to clear hepatitis B virus infection from hepatocytes. Using
HBV-transgenic mice as well as viral vectors for hepatocyte
transduction with HBV (AdHBV and AAV-HBV), we show
that iMATE-induced expansion and functional maturation
of HBV-specific CD8 T cells is operative in the control of
HBV infection. We provide evidence that iMATE induction
is a critical so far not recognized step in anti-viral immunity
for control of viral infection in the liver. iMATEs expand 30
to 50-fold those CD8 T cells in the liver that were activated
previously in lymphoid tissues and then localized to the liver.
Even after splenectomy and blockade of lymphocyte egress
from lymph nodes, iMATEs expanded antigen-experienced T
cells. The combination of therapeutic vaccination approaches,
such as DNA-vaccination and protein prime followed by MVA
boost vaccination, in preclinical models of chronic hepatitis
B together with iMATE induction achieved functional control
of HBV infection. Mechanistically, we found that upon iMATE
induction T cells rapidly upregulated GzmB expression in the
liver. Conclusion: Thus, combination of protein prime - MVA
boost therapeutic vaccination protocols with iMATE induction
for local massive expansion and increased cytotoxic potential
of HBV-specific CD8 T cells overcomes hepatic immune
regulatory cues and allows for control of HBV replication in
preclinical models of chronic hepatitis B. |
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发表于 2018-10-26 14:46