Letter to the Editor: Entecavir Treatment Restores the Anti-HBV Immune response?

TO THE EDITOR:

With great interest, we read the manuscript by De Pasquale et al.( ) They convincingly showed that dendritic cells (DCs), generated in vitro from monocytes of patients with HBV, have a detrimental effect on the function of natural killer (NK) cells, leading to the insufficient anti‐HBV response observed in patients with chronic HBV. However, many years ago, we conducted a similar study.( ) In our study, we did not use monocyte‐derived DCs, but only ex vivo isolated blood dendritic cell antigen 1–positive (BDCA1+) DCs, and examined the DC–NK interaction in a larger and prospectively designed cohort study of 39 patients with HBV and 16 healthy controls. Given the complexity of these type of studies, we were pleased to learn that the study by De Pasquale et al. supported our earlier findings.

In one challenging experiment of our earlier study, we co‐cultured pretreatment NK cells with BDCA1+ DCs isolated from the same patient before and during 6 months of entecavir treatment. We observed that antiviral therapy enhanced the production of multiple DC‐derived cytokines (including IL‐12p70), and consequently improved the anti‐HBV‐associated DC–NK cell function. Our ex vivo experiments clearly show, as in the current study by De Paquale et al., that altered DC function in patients with chronic HBV leads to impairment of NK cell activity, which can be reversed by antiviral treatment.

We were intrigued to read that a soluble factor in the serum of patients with chronic HBV impaired co‐cultured DC function, something not observed when using sera from entecavir‐treated patients. De Pasquale et al. suggested a role for IL‐10; however, many cytokines are known to respond to entecavir treatment. For instance, during entecavir treatment, plasma levels of immune‐suppressive TGF‐β1 and pro‐inflammatory IL‐17 and IL‐23 gradually decrease, while IL‐4‐stimulating and DC‐stimulating interferon‐γ increase.( ) We conclude that the soluble serum factor that modulates the DC–NK cross talk leading to impaired NK cell activity is not just IL‐10, but rather a complex serum cytokine milieu, deserving of better characterization.