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P0485
FUNCTIONAL IMMUNE RESTORATION CORRELATES WITH
HBsAg DECLINE AND MAY PREDICT TREATMENT RESPONSE
ON SEQUENTIAL NUC THERAPY IN CHRONIC HEPATITIS B
U.S. Gill1, D. Peppa2, L. Micco2, H.D. Singh2, G.R. Foster1,
M.K. Maini2, P.T. Kennedy1. 1Hepatology Unit, Centre for Digestive
Diseases, Blizard Institute, Barts and The London SMD, QMUL,
2Division of Infection & Immunity, UCL, London, United Kingdom
E-mail: [email protected]
Background and Aims: Sequential/combined therapeutic approaches
comprising Pegylated-Interferon (Peg-IFNa) and nucleot(
s)ide analogues (NUC) are being given greater consideration
as treatment strategies for chronic hepatitis B (CHB) to achieve
HBsAg loss. We demonstrated boosting of NK cells in eAg− patients
treated with Peg-IFNa (Micco et al, J. Hepatol, 2013), and postulated
this effect could be maintained with sequential NUC therapy.
Differential NK cell responses in patients receiving sequential NUCs
were analysed and correlated with HBsAg response, to elucidate a
possible treatment advantage with Peg-IFNa exposure.
Methods: PBMC from 18 eAg+ patients during Peg-IFNa
therapy were utlised. 9/18 patients considered Peg-IFNa nonresponders
after 48-weeks therapy progressed to sequential
NUCs and were followed until virally suppressed. Phenotypic
and functional analysis of NK cell subsets was performed by
multicolour flow-cytometry and findings correlated with ontherapy
HBsAg changes.
Results: Peg-IFNa expanded CD56bright NK cells by 3-fold
(p = 0.0001) which was maintained on sequential therapy. NK cell
receptor expression was analysed. All receptors, except NKG2C,
were maintained on sequential NUCs, with marked augmentation in
the expression of NKp30 and NKp46 on CD56bright NK cells (p ≤ 0.05).
These NK cells maintained their ability to degranulate and produce
IFNg during sequential therapy, functional restorations not seen on
NUCs alone (p = 0.0001 and 0.002 respectively). TRAIL expression
was analysed; this decreased on sequential NUCs, but remained
higher than baseline. 6/9 patients had significant declines in HBsAg
(>0.5 log10 IU/ml) on sequential NUCs. We noted that only these
patients showed the ability to increase the proportion of functional
NK cells (IFNg+ and CD107+) on sequential NUCs. Additionally only
these responders demonstrated a reduction in TRAIL expression on
sequential NUCs, compared to those without HBsAg decline, who
showed the reverse.
Conclusions: Restoration of NK cell cytotoxic/effector functions is
seen on sequential therapy, but only in those patients with HBsAg
decline. Lower expression of TRAIL also correlates with treatment
response, in line with our finding that TRAIL+ NK cells can delete
antiviral T-cells (Peppa et al, JEM 2013). IFNg, CD107 and TRAIL
expression on NK cells may predict those patients who are likely
to demonstrate HBsAg decline on sequential therapy. Given these
findings, the TRAIL pathway may be a potential future target in
order to improve treatment outcomes in CHB.
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发表于 2015-4-20 17:00