Abstract
Pegylated interferon α-2a (Peg-IFN-α) represents a therapeutic alternative to the prolonged use of nucleos(t)ide analog (NA) in chronic hepatitis B (CHB) infection. The mechanisms leading to a positive clinical outcome remain unclear. As immune responses are critical for virus control, we investigated the effects of Peg-IFN-α on both innate and adaptive immunity, and related it to the clinical evolution. The phenotypic and functional features of the dendritic cells (DCs), natural killer (NK) cells and HBV-specific CD4/CD8 T cells were analyzed in HBeAg-negative CHB patients treated for 48-weeks with NA alone or together with Peg-IFN-α, before, during and up to 2-years after therapy. Peg-IFN-α induced an early activation of DCs, a potent expansion of the CD56bright NK subset, and enhanced the activation and functionality of the CD56dim NK subset. Peg-IFN-α triggered an increase in the frequencies of Th1- and Th17-oriented HBV-specific CD4/CD8 T cells. Peg-IFN-α reversed the unresponsiveness of patients to a specific stimulation. Most of the parameters returned to baseline after the stop of Peg-IFN-α therapy. Peg-IFN-α impacts both innate and adaptive immunity, overcoming dysfunctional immune responses in CHB patients. These modulations were not associated with seroconversion, which questioned the benefit of the add-on Peg-IFN-α treatment.
Highlights
Pegylated interferon α-2a (Peg-IFN-α) therapy represents a promising therapeutic alternative to the prolonged use of nucleos(t)ide analogs (NA) in chronic hepatitis B (CHB) infection [1,2,3,4]
The virus may actively alter the function of plasmacytoid dendritic cells (DCs) [5], leading to a failure of the subsequent pDC-natural killer (NK) cross-talk in CHB patients [6]
HBV-specific T-cell responses are often weak in patients who evolve toward chronic HBV infection [8], whereas multi-specific and vigorous HBV-specific T-cell responses directed toward epitopes located within the major HBV proteins [i.e. the nucleoscapsid (HBc), the surface antigen (HBs), the HBx antigen, and the polymerase (POL)] are required to successfully control HBV infection [9]
Summary
Pegylated interferon α-2a (Peg-IFN-α) therapy represents a promising therapeutic alternative to the prolonged use of nucleos(t)ide analogs (NA) in chronic hepatitis B (CHB) infection [1,2,3,4]. Peg-IFN-α potentially leads to HBsAg seroconversion, its mechanisms of immunomodulation remain poorly known. Dysfunctions in dendritic cells (DCs), natural killer (NK) cells and T cells have been identified in patients with CHB infection. The virus may actively alter the function of plasmacytoid DCs (pDCs) [5], leading to a failure of the subsequent pDC-NK cross-talk in CHB patients [6]. HBV-specific T-cell responses are often weak in patients who evolve toward chronic HBV infection [8], whereas multi-specific and vigorous HBV-specific T-cell responses directed toward epitopes located within the major HBV proteins [i.e. the nucleoscapsid (HBc), the surface antigen (HBs), the HBx antigen, and the polymerase (POL)] are required to successfully control HBV infection [9]
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