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586
Silencing hepatitis B virus (HBV) gene expression in the
liver by RNAi prevents HBV-specific CD8 T cell exhaustion
Keigo Kawashima1,2, Masanori Isogawa1, Satoru Saito2, Yasuhito
Tanaka1; 1Nagoya City University Graduate School of Medical
Science, Nagoya, Japan; 2Yokohama City University School of
Medicine, Yokohama, Japan
[Background and Aims] Hepatitis B virus (HBV) specific CD8 T
cell responses are required for HBV clearance. However, their
effector functions are usually impaired in chronic HBV patients,
presumably reflecting functional exhaustion due to excessive
HBV antigen expressions in the liver. Thus, the objective of
this study is to examine whether antigen reduction induces
functional HBV-specific CD8 T cells. [Methods] HBV transgenic
(HBV-Tg) mice were adoptively transferred with spleen cells
from T cell receptor (TCR) transgenic mice that express a TCR
specific for core 93-100 epitope (COR93), and then treated
with HBV-specific siRNA (siHBV) covered with lipid nano particles
or control siRNA (siCTRL) on day 3 (expansion phase)
or day 17 (contraction phase). Intrahepatic HBV-specific CD8
T cells were analyzed for their proliferation and IFN-γ production,
and were associated with serum HBV antigen levels,
ALT activity, and intrahepatic HBV-mRNA expression. [Results]
SiHBV treatment strongly suppressed serum HBsAg level as well
as intrahepatic HBV-mRNA expression. When recipients were
treated with siHBV during expansion phase, the proliferation of
HBV-specific CD8 T cells was reduced in association with HBVmRNA
expression, resulting in lower serum ALT activity. However,
HBV-specific CD8 T cells did not acquire IFN-γ producing
ability, suggesting that antigen suppression alone was insufficient
to induce T cell effector functions. We then examined
whether intrahepatic HBV antigen suppression allows HBV-specific
T cells to differentiate into effector T cells upon peripheral
immunization. We immunized HBV-Tg mice by subcutaneously
injecting COR93 peptide 4 days after siRNA treatment (day 3
or day 17), and analyzed HBV-specific CD8 T cell responses 7
days later. Again the proliferation of HBV-specific CD8 T cells
was reduced when HBV antigen expression was suppressed
during T cell expansion phase (day 3). Importantly, a larger
fraction of HBV-specific CD8 T cells now acquired IFN-γ producing
ability in the siHBV treated HBV-Tg mice than in the
siCTRL treated animals. In contrast, neither the reduction of T
cell proliferation nor the induction of IFN-γ was observed when
siHBV was administered during T cell contraction phase (day
17). [Conclusions] RNAi treatment may represent a promising
therapeutic approach to treat chronic HBV patients as HBV
antigen reduction during expansion phase prevents HBV-specific
T cells from exhaustion. However, the degree of intrahepatic
T cell exhaustion is regulated by the duration of antigen
recognition, and more robust immunological interventions are
required to restore T cell responsiveness once exhaustion is
established.
Disclosures:
Yasuhito Tanaka - Grant/Research Support: Chugai Pharmaceutical CO., LTD.,
MSD, abbvie, Bristol-Myers Squibb; Speaking and Teaching: Bristol-Myers
Squibb
The following people have nothing to disclose: Keigo Kawashima, Masanori
Isogawa, Satoru Saito
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发表于 2016-10-12 18:47