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* Research Center of Biological Therapy, Beijing 302 Hospital, Beijing, China;
Center for Infection and Immunity, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, China; and
Department of Dermatology, Department of Oncology, and the Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21231
Although dysfunctional dendritic cells contribute to inadequate adaptive immunity in chronic hepatitis B (CHB), underlying molecular mechanisms remain largely undefined. In this study, we examined B7-H1 expression on circulating myeloid dendritic cells (mDCs) in 46 CHB patients, 10 autoimmune hepatitis patients, and 10 healthy subjects as control. We found that B7-H1 expression is significantly up-regulated on circulating mDCs of CHB and autoimmune hepatitis patients compared with healthy individuals. The B7-H1 up-regulation was significantly correlated with an elevation of serum alanine aminotransaminase levels and plasma viral load. In addition, in vitro, both IFN-
and IFN-
could strongly stimulate mDCs to express B7-H1. More importantly, elevated B7-H1 expression is also closely associated with the suppression of T cell immune function. In vitro blockade of B7-H1 signaling could not only down-regulate IL-10 and up-regulate IL-12 production by mDCs, but also enhance mDC-mediated allostimulatory capacity and cytokine production of T cells. Blockade of B7-H1 signaling could improve hepatitis B c Ag-pulsed monocyte-derived DC-induced IFN- production by autologous hepatitis B virus-specific T cells. These new findings suggested that chronic inflammation may contribute to B7-H1 up-regulation on mDCs in CHB patients, which potentially cause defective hepatitis B virus-specific T cell function and viral persistence. Our findings further support the notion that the blockade of B7-H1 may represent a novel therapeutic approach for this disease.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the National Key Basic Research Program of China (2006CB504305), the National Outstanding Youth Foundation of China (30525042), and the National Institutes of Health (CA97085).
2 L.C. and Z.Z. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Fu-Sheng Wang, Research Centre for Biological Therapy, Beijing Institute of Infectious Diseases, Beijing 302 Hospital, 100 Xi Si Huan Middle Road, Beijing, China or Dr. Sheng-Dian Wang, Center for Infection and Immunity, National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Chaoyang District, Beijing, China. E-mail addresses: fswang{at}public.bta.net.cn or sdwang{at}moon.ibp.ac.cn
4 Abbreviations used in this paper: HBV, hepatitis B virus; CHB, chronic hepatitis B; DC, dendritic cell; mDC, myeloid DC; HCV, hepatitis C virus; PD, programmed death; ALT, alanine aminotransferase; IT, immune tolerant; IA, immune active; HC, healthy control; AIH, autoimmune hepatitis; MoDC, monocyte-derived DC; HBcAg, hepatitis B c Ag.
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