Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV†

Abstract

In patients with chronic hepatitis B virus (HBV), 2 predominant precursor dendritic cell (DC) subtypes, the myeloid dendritic cell (mDC) and the plasmacytoid dendritic cell (pDC), were recently found to be functionally impaired. HBV DNA was found to be present in the DC subtypes, but no viral replication could be detected. The question remains whether simply the presence of the virus and viral proteins causes this dysfunction of DCs. To address this issue, the effect of viral load reduction resulting from treatment with the nucleotide analogue adefovir dipivoxil on the number and functionality of circulating DCs was studied during 6 months of treatment. Treatment resulted in a mean 5 log 10 decrease in the viral load and normalization of alanine aminotransferase within 3 months. The number of mDCs, but not of pDCs, increased significantly over 6 months of treatment to a level comparable to that of uninfected healthy controls. The allostimulatory capacity of isolated and in vitro matured mDCs increased significantly after 3 months of treatment. Accordingly, mDCs exhibited an increased capacity to produce tumor necrosis factor alpha and interleukin-12 after 3-6 months of treatment. There was no change in interferon alpha production by pDCs during treatment. In conclusion, adefovir treatment results in an improvement in the number and functionality of mDCs, but not of pDCs. Our findings provide clues for the reasons why current antiviral therapy does not lead to consistently sustained viral eradication. T oday, more than 400 million people are chronically infected with hepatitis B virus (HBV) and are at risk of developing cirrhosis or hepatocellular carcinoma. 1,2 Chronic HBV infection is the result of a complex interaction between a replicating noncytopathic virus and a down-regulated antiviral immune response. To recover from an HBV infection, both strong humoral and cellular immune responses are required. During an acute infection, class I-and class II-restricted T-cell responses to the virus are vigorous, polyclonal, and multispecific. [3][4][5] Such responses are relatively weak and more narrowly focused in chronically infected patients. 6,7 Dendritic cells (DCs) play an important role in the induction of specific T-cell responses. We recently demonstrated functional impairment of the myeloid dendritic cells (mDCs) and plasmacytoid dendritic cells (pDCs) of patients with chronic HBV infection compared to healthy volunteers. 8 We showed reduced maturation, T-cell stimulatory capacity, and tumor necrosis factor alpha (TNF-␣) production by mDCs and reduced interferon alpha (IFN-␣) production by pDCs. In addition, we have recently shown that regulatory T cells contribute to the impaired immune response in patients with chronic HBV. 9 These regulatory T cells were found to suppress HBV-specific T-cell responses. Regulatory T cells can be induced by immature DCs. 10 Together, these data suggest an important link between impaired DC function and insufficient T-cell response in chronic HBV infection.The mechanism by w...

Dissecting the dendritic cell controversy in chronic hepatitis B virus infection

“…Pediatric patients with immune active disease or infants born to mothers with .5310 7 copies/ml HBV also showed a reduced pDC frequency in the blood. 12,24 In two studies where reduced frequencies were observed in adult patients, the pDC numbers recovered with antiviral therapy, 18,25 again suggesting that DC frequency can be restored with effective treatment.…”

“…Zhang et al 12 reported a lower frequency of mDCs in the blood of immune active pediatric patients, but not in those who were immune-tolerant. A study by van der Molen et al 18 found that mDC frequencies were reduced in chronic HBV patients. However, mDC frequency could be returned to the level of healthy donors with antiviral therapy.…”

Improved survival ratios correlate with myeloid dendritic cell restoration in acute-on-chronic liver failure patients receiving methylprednisolone therapy

“…Recent studies have demonstrated the functional impairment of mDCs and pDCs in patients with chronic HBV infection. [17][18][19] Notably, these dendritic cells accumulate mostly in the liver of ACLF patients; 7,8,14 however, any correlation between the DCs and corticosteroid efficacy is unknown.…”

Adefovir dipivoxil modulates cytokine expression in Th1/Th2 cells in patients with chronic hepatitis B

“…ADV has a broad-spectrum of antiviral activity, targeting herpesvirus, retroviruses and hepadnaviruses (7,20) and potently inhibits the replication of wild-type HBV and lamivudine-resistant strains (3). In this study, the serum HBV DNA levels in the majority (77.3%, 17/22) of CHB patients were decreased to the levels less than the detection limit following 24 weeks of ADV treatment, although certain patients, e.g., Patient 3, had no or little response to the ADV treatment, which may be associated with ADV resistance (21).…”

“…CHB is the result of a complex interaction between a replicating non-cytopathic virus and a down-regulated anti-viral immune response of the patient. Strong humoral and cellular immune responses are required for complete recovery from CHB (3). Therefore, there is an increasing interest in investigating the host immune response to antiviral therapy in order to develop novel therapeutic approaches or to improve clinically available agents.…”