Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B

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• 作者：Lorenzo Micco¹ ; ² ; Dimitra Peppa¹ ; Elisabetta Loggi² ; Anna Schurich¹ ; Lucy Jefferson¹ ; Carmela Cursaro² ; Arianna Martello Panno² ; Mauro Bernardi² ; Christian Brander³ ; Florian Bihl⁴ ; ⁵ ; Pietro Andreone² ; Mala K. Maini¹ ; ^{m.maini@ucl.ac.uk}
• 关键词：ALT ; Alanine transaminase ; HBV ; Hepatitis B virus ; CHB ; Chronic HBV infection ; IFN-¦Á ; interferon-alpha ; IFN-¦Ã ; interferon-gamma ; TRAIL ; TNF-related apoptosis inducing ligand
• 刊名：Journal of Hepatology
• 出版年：2013
• 出版时间：February, 2013
• 年：2013
• 卷：58
• 期：2
• 页码：225-233
• 全文大小：916 K

文摘

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Background & Aims

A better understanding of the immunomodulatory effects of PegIFN¦Á therapy could allow more rational optimisation of future therapeutic approaches in chronic HBV infection. In this study, we evaluated dynamic changes in the innate and adaptive arms of the immune system induced by PegIFN¦Á.

Methods

PBMC were obtained from a cohort of patients with eAg-negative CHB before, during and after PegIFN¦Á treatment. The number, phenotype and function of global and virus-specific T cells and NK cells were analyzed by flow cytometry and serum cytokines by ELISA or CBA.

Results

The absolute number of CD8 T cells was strikingly reduced on PegIFN¦Á therapy (p <0.001), with a predominant loss of end-stage effectors, including CMV-specific CD8 T cells. There was no significant recovery of the exhausted HBV-specific CD8 T cell response. By contrast, PegIFN¦Á was able to potently and cumulatively drive the proliferation and expansion in absolute numbers of CD56^bright NK cell numbers (p <0.001), with induction of the pro-proliferative cytokine IL-15. Expanded CD56^bright NK cells showed enhanced expression of activation markers and the activating receptor NKp46, accompanied by augmentation of TRAIL and IFN-¦Ã expression (p <0.001). Peak virological response (temporal within individual patients and cross-sectional within the cohort) correlated with the degree of expansion of functional CD56^bright NK cells.

Conclusions

IFN-¦Á mediates divergent effects on the innate and adaptive arms of the immune system in vivo. The efficacy of PegIFN¦Á may be limited by its depleting effect on CD8 T cells; conversely, it can cumulatively drive proliferation, activation and antiviral potential of CD56^bright NK cells.