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Functional innate immune responses are restored with sequential NUC therapy following Pegylated Interferon-Alpha exposure and not with NUC monotherapy in Chronic Hepatitis B
Upkar S. Gill1, Dimitra Peppa2, Harsimran D. Singh2, Lorenzo Micco2, Graham R. Foster1, Mala K. Maini2, Patrick T. Kennedy1;
1Hepatology Unit, Centre for Digestive Diseases, Blizard Institute, Barts and The London, School of Medicine & Dentistry, QMUL, London, United Kingdom; 2Division of Infection & Immunity, UCL, London, United Kingdom
INTRODUCTION: Treatment strategies in Chronic Hepatitis B (CHB) are now focused on achieving HBsAg loss; therefore greater consideration is being given to combined/sequential therapeutic approaches comprising Pegylated-Interferon (PEG-IFN-α) and nucleot(s)ide analogue (NUC) therapy, to achieve this goal. We previously demonstrated boosting of NK cell responses in eAg- patients treated with PEG-IFN-α (Micco et al, J. Hepatol, 2013), and postulated that this effect could be maintained with sequential NUC therapy, representing a superior strategy to NUC monotherapy. Differential NK cell responses in patients receiving a sequential NUC were compared to patients on NUC monotherapy to determine if there was a treatment advantage with PEG-IFN-α exposure.
PATIENTS & METHODS: PBMC from 18 eAg+ patients during PEG-IFN-α therapy were utlised. 10/18 patients considered PEG-IFN-α non-responders after 48 weeks therapy progressed to sequential NUC therapy and were followed until virally suppressed. NUC monother-apy patients, without prior PEG-IFN-α exposure, were analysed for comparison. Phenotypic and functional analysis of NK cell subsets was performed by multicolour flow-cytometry.
RESULTS: PEG-IFN-α expanded CD56bright NK cells by 3-fold (p=0.0001); this was maintained on sequential therapy but not seen with NUCs alone (p=0.03). NK cell expression of C-Type lectin and natural cytotoxicity receptors was analysed. All receptors, except NKG2D, were expressed at significantly higher levels on sequential NUCs vs. NUC monotherapy (p=<0.05), with marked augmentation in the expression of NKp30 and NKp46 on CD56bright NK cells (p=0.0001 & 0.002 respectively). The proportion of CD56bright NK cells expressing TRAIL was 3-fold higher on sequential NUC therapy compared with NUC monotherapy (p=0.007). These NK cells during sequential therapy demonstrated ability to degranulate and produce IFN-γ; functional restorations not achieved on NUCs alone (p=0.0001 & 0.002 respectively). These changes were more dramatic in patients demonstrating eAg seroconversion +/− sAg decline on sequential NUCs
CONSLUSIONS: The potent expansion of activated CD56bright NK cells induced by PEG-IFN-α is sustained on sequential NUC therapy, with high expression of NKp30, NKp46 and TRAIL when compared to NUCs alone. Restoration of NK cell cytotoxic/effector functions on sequential therapy is seen compared to NUC monother-apy. PEG-IFN-α non-responders exhibit innate boosting which is maintained with functional innate restoration on sequential NUC therapy. Further work is being undertaken to determine if this priming effect is present with shorter courses of PEG-IFN-α.
Disclosures:
Graham R. Foster - Advisory Committees or Review Panels: GlaxoSmithKline, Novartis, Boehringer Ingelheim, Tibotec, Chughai, Gilead, Janssen, Idenix, GlaxoSmithKline, Novartis, Roche, Tibotec, Chughai, Gilead, Merck, Janssen, Idenix, BMS; Board Membership: Boehringer Ingelheim; Grant/Research Support: Chughai, Roche, Chughai; Speaking and Teaching: Roche, Gilead, Tibo-tec, Merck, BMS, Boehringer Ingelheim, Gilead, Janssen
Mala K. Maini - Advisory Committees or Review Panels: Roche; Consulting: Transgene, ITS; Grant/Research Support: BMS; Speaking and Teaching: BMS
Patrick T. Kennedy - Grant/Research Support: Roche, Gilead; Speaking and Teaching: BMS, Roche, Gilead
The following people have nothing to disclose: Upkar S. Gill, Dimitra Peppa, Harsimran D. Singh, Lorenzo Micco
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发表于 2014-10-13 07:51
