title: Differential boosting of innate and adaptive antiviral responses during pegylated-interferon-alpha therapy of chronic hepatitis B.
abstract: OBJECTIVE
  A better understanding of the immunomodulatory effects of PegIFNα 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 PegIFNα.
  
  
  METHODS
  PBMC were obtained from a cohort of patients with eAg-negative CHB before, during and after PegIFNα 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 PegIFNα 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, PegIFNα 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-γ 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-α mediates divergent effects on the innate and adaptive arms of the immune system in vivo. The efficacy of PegIFNα 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.
authors.affiliation: Division of Infection and Immunity, UCL, London, UK.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Micco
authors.forename: Dimitra
authors.initials: D
authors.lastname: Peppa
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Loggi
authors.forename: Anna
authors.initials: A
authors.lastname: Schurich
authors.forename: Lucy
authors.initials: L
authors.lastname: Jefferson
authors.forename: Carmela
authors.initials: C
authors.lastname: Cursaro
authors.forename: Arianna Martello
authors.initials: AM
authors.lastname: Panno
authors.forename: Mauro
authors.initials: M
authors.lastname: Bernardi
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: Florian
authors.initials: F
authors.lastname: Bihl
authors.forename: Pietro
authors.initials: P
authors.lastname: Andreone
authors.forename: Mala K
authors.initials: MK
authors.lastname: Maini
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000502:physiology*; D000328:Adult; D000998:Antiviral Agents / Q000494:pharmacology / Q000627:therapeutic use*; D019002:CD56 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D015331:Cohort Studies; D005260:Female; D006515:Hepatitis B virus / Q000276:immunology*; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology*; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use*; D019409:Interleukin-15 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011092:Polyethylene Glycols / Q000494:pharmacology / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000998:Antiviral Agents; D019002:CD56 Antigen; D016898:Interferon-alpha; D019409:Interleukin-15; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a