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Analysis of innate and adaptive host immunity during combination therapy with peginterferon Lambda-1a and Entecavir in patients with HBeAg(+) chronic hepatitis B
Sandra Phillips1, Sameer Mistry1, Antonio Riva1, Helen Cooksley1,
Stefan Zeuzem2, Clive Woffendin3, Pei-Jer Chen4, Cheng-Yuan
Peng5, Ting-Tsung Chang6, Stefan Lueth7, Robert J. de Knegt8,
Moon Seok Choi9, Heiner Wedemeyer10, Michael Dao11, Chang
Wook Kim12, Heng C. Chu13, Megan Wind-Rotolo14, Roger Williams1,
Elizabeth L. Cooney14, Shilpa Chokshi1;
1Institute of Hepatology, Foundation for Liver Research, London, United Kingdom;
2Johann Wolfgang Goethe University Medical Center, Frankfurt, Germany;
3Oregon Clinical and Translational Research Institute, Portland, OR;
4National Taiwan University Hospital, Taipei, Taiwan;
5China Medical University Hospital, Taichung, Taiwan;
6National Chen Kung University Hospital, Tainan, Taiwan;
7University of Hamburg, Hamburg, Germany;
8Erasmus University, Rotterdam, Netherlands;
9Sungkyunkwan University, Seoul, Republic of Korea;
10Hannover Medical School, Hannover, Germany;
11Precision Diagnostic Laboratory, Santa Ana, CA;
12The Catholic Universityof Korea, Seoul, Republic of Korea;
13Tri-Service General Hospital, Taipei, Taiwan;
14Research and Development, Bristol-Myers Squibb, Wallingford, CT
Background/Aims:
Multiple in vitro studies have been conducted characterizing the innate antiviral effects of IFNλ. However to date there are limited data regarding the impact of peginterferon Lambda-1a (Lambda), which has shown anti-HBV activity both in vitro and in vivo, on host immune responses in vivo. In this study we aimed to longitudinally assess the effect of Lambda on innate and adaptive immunity when administered in combination with Entecavir (ETV) employing a sequential dosing approach in treatment-naive HBeAg(+) chronic hepatitis B (CHB) patients.
Methods:
NK-cell frequency, phenotype, expression of inhibitory/activating signatures and
function by IFNγ production and cytotoxicity were measured by FACS. Expression of immunoinhibitory receptors on HBV-specific CD4+/CD8+ T-cells were measured by FACS. Ex-vivo frequency of HBV-specific CD4+/CD8+ T-cells producing IFNγ and IL-10 to genotype-specific HBcAg/HBsAg peptide pools were quantified by Elispot assays and intracellular cytokine staining. Levels of circulating T-regulatory cells were also assessed. Immunological analyses were performed at 9 timepoints(TP) through the study period including Baseline, TW4,
TW8, TW12 TW16,TW24,TW36 and 2 subsequent follow up visits (TW60, TW84). Virological and clinical parameters were also measured at each TP and correlated with immunological assessments.
Results:
In this study, a total of 13 subjects received combination Lambda plus ETV. The population was of mean age 31.2 years, 77% male and 92% Asian. At baseline, mean laboratory values showed: HBV DNA 8.3 log10 IU/mL, qHBsAg 4.6 IU/mL and ALT 88 U/L. The addition of Lambda to ETV was not associated with recovery of HBV-specific CD4/CD8+ T-cells producing IFNγ. From baseline and through the study there was a predominance of HBV-specific IL-10 production and an increasing expression of PD1 particularly on CD4+ T-cells. In contrast, addition of Lambda induced potent activation of NK-cell functionality with marked augmentation of IFNγ production, degranulation and ability to kill target cells.
This was associated with upregulation of activating receptor NKG2D on CD56brightNK-cells but no changes in expression of PD1 or apoptosis-inducing TRAIL were observed. The frequency of T-regulatory cells was low (<2%) throughout the study.
Conclusions:
The use of Lambda in combination with ETV in HBeAg(+) CHB patients impacts the innate and adaptive immune responses differentially. Similar to the immunological studies conducted in pegIFNα-treated CHB patients, Lambda does not seem to reconstitute the impaired virus-specific T-cell response but does induce potent antiviral NK-cell activation and functionality in vivo.
Disclosures:
Stefan Zeuzem - Consulting: Abbvie, Boehringer Ingelheim GmbH, Bristol-Myers
Squibb Co., Gilead, Novartis Pharmaceuticals, Merck & Co., Idenix, Janssen,
Roche Pharma AG, Vertex Pharmaceuticals
Pei-Jer Chen - Advisory Committees or Review Panels: BMS, GSK, BMS, GSK,
Medigene; Independent Contractor: J & J; Speaking and Teaching: Roche, Roche
Ting-Tsung Chang - Advisory Committees or Review Panels: Bristol-Myers Squibb;
Speaking and Teaching: Bristol-Myers Squibb
Stefan Lueth - Advisory Committees or Review Panels: BMS, Gilead, MSD, Janssen
Robert J. de Knegt - Advisory Committees or Review Panels: MSD, Roche,
Norgine, Janssen Cilag; Grant/Research Support: Gilead, MSD, Roche, Janssen
Cilag, BMS; Speaking and Teaching: Gilead, MSD, Roche, Janssen Cilag
Heiner Wedemeyer - Advisory Committees or Review Panels: Transgene, MSD,
Roche, Gilead, Abbott, BMS, Falk, Abbvie, Novartis, GSK; Grant/Research
Support: MSD, Novartis, Gilead, Roche, Abbott; Speaking and Teaching: BMS,
MSD, Novartis, ITF, Abbvie, Gilead
Chang Wook Kim - Consulting: Gilead, MSD; Grant/Research Support: BMS,
Handok, Pharmicell, Pharmaking; Speaking and Teaching: BMS, Donga, Daewoong
Megan Wind-Rotolo - Employment: Bristol-Myers Squibb; Stock Shareholder:
Bristol-Myers Squibb
Elizabeth L. Cooney - Employment: Bristol-Myers Squibb Inc; Stock Shareholder:
Bristol-Myers Squibb Inc
The following people have nothing to disclose: Sandra Phillips, Sameer Mistry,
Antonio Riva, Helen Cooksley, Clive Woffendin, Cheng-Yuan Peng, Moon Seok
Choi, Michael Dao, Heng C. Chu, Roger Williams, Shilpa Chokshi
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发表于 2014-10-4 17:56
