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690
MODULATING ANTIGEN PRESENTATION IN HEPATITIS B VIRUS
INFECTED HEPATOCYTES WITH DRUG CLASSES IN CLINICAL
DEVELOPMENT IMPACTS CD8 T CELL RECOGNITION
Adrian Kuipery, University Health Network; Immunology,
University of Toronto; Toronto Center for Liver Disease,
Toronto General Hospital Research Institute, Harry L. A.
Janssen, Toronto Centre for Liver Disease, Francis Family
Liver Clinic, Toronto General Hospital and Adam J. Gehring,
Toronto Centre for Liver Disease, Toronto General Hospital
Research Institute, University Health Network
Background: Hepatitis B virus (HBV) specific CD8 T cell
immunity is essential for the control of HBV infection. Short
interfering RNA (siRNA) and immunomodulatory drugs in
clinical development for chronic Hepatitis B (CHB) have the
potential to modulate antigen expression and hepatocyte
antigen presentation The impact of these treatments on CD8
T recognition of infected hepatocytes remains to be clarified.
We hypothesize that siRNA and immunomodulatory drugs
alter presentation of HBV antigens, impacting CD8 T cell
recognition Methods: HepG2-NTCP cells were infected with
HBV and treated with siRNA targeting all HBV transcripts, or
exposed to conditioned media harvested after 24h treatment of
PBMC with the TLR-8 agonist, TL:506. Infected HepG2-NTCP
cells were then co-cultured with HBV-specific CD8 T cells
recognizing immunodominant epitopes C18-27 and S183-
191 to measure antigen presentation Results: Treatment
of HBV infected HepG2-NTCP cells with HBV-specific siRNA
inhibited HBV replication and suppressed HBV antigen
production Reduced antigen production suppressed CD8 T
cell recognition by 80% as early as 2 days post treatment
CD8 T cell recognition began to recover by 8 days post siRNA
treatment but was still suppressed by 48 1%, consistent with
the slow recovery of antigen expression in infected HepG2-
NTCP To investigate effects of immunomodulation, we
stimulated PBMCs with TL8:506. TL8:506 stimulation strongly
induced proinflammatory cytokines, including IFN-γ, IL-1β,
IFN-λ, and TNF-α. When infected HepG2-NTCP were cultured
with conditioned media, CD8 T cell recognition of both the
S183-191 and C18-27 epitopes was enhanced, resulting in a
15 and 3 fold increase in the proportion of IFN-y positive CD8
T cells, respectively Conclusion: Therapies in development
for the treatment of CHB alter CD8 T cell recognition of HBV
infected cells A deeper understanding of the effects of new
drugs on interactions between hepatocytes and CD8 T cells
may help optimize combination therapies. |
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发表于 2019-11-1 19:00