Production of antibody to hepatitis B surface antigen (anti-HBs) by murine hepatitis B virus carriers: neonatal tolerance versus antigen presentation by dendritic cells.
The inability of hepatitis B virus (HBV) transgenic mice, which express abundant hepatitis B surface antigen (HBsAg) in sera from the neonatal period onwards, to produce antibody to HBsAg (anti-HBs) is considered to be due to defective function of lymphocytes. The defective function is thought to result from neonatal tolerance because antigenic challenge during the neonatal period is considered to be a tolerogenic event rather than an immunogenic one. However, a series of mixed culture experiments in vitro showed that lymphocytes taken from transgenic mice that had been injected with HBsAg in complete Freund's adjuvant (CFA) constitutively produced anti-HBs when cultured with dendritic cells from age-, sex- and major histocompatibility complex (MHC)-matched normal mice, but not when cultured with dendritic cells from transgenic mice. The expression of major histocompatibility complex (MHC) class II and B 7.2 (CD86) antigens on dendritic cells was significantly lower in transgenic mice compared with the same from the normal mice (P < 0.05). Treatment of transgenic mice with interferon-gamma (IFN-gamma) resulted in up-regulation of MHC class II on dendritic cells, and lymphocytes from HBsAg-injected transgenic mice produced anti-HBs in vitro when cultured with dendritic cells from IFN-gamma-treated transgenic mice, but not when cultured with the dendritic cells from untreated transgenic mice. These experiments have shown that defective function of antigen-presenting cells (APC), not immunogenic tolerance, is responsible for the inability of murine HBV-carriers to produce anti-HBs. Production of anti-HBs by lymphocytes from HBsAg-injected transgenic mice in the presence of dendritic cells that express higher levels of MHC class II and CD86 antigens has inspired optimism that a more effective vaccine therapy can be developed for chronic HBV-carriers, injecting vaccine containing HBsAg with modulator(s) of APC function of dendritic cells.
Kurose
K
K
Third Department of Internal Medicine, Ehime University of Medicine, Japan.
Akbar
S M
SM
Yamamoto
K
K
Onji
M
M
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D002353:Carrier State / Q000276:immunology*; D018929:Cell Culture Techniques; D003713:Dendritic Cells / Q000276:immunology*; D006509:Hepatitis B / Q000276:immunology*; D006510:Hepatitis B Antibodies / Q000096:biosynthesis*; D006514:Hepatitis B Surface Antigens / Q000276:immunology*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000276:immunology
D001323:Autoantibodies; D006510:Hepatitis B Antibodies; D006514:Hepatitis B Surface Antigens; D007371:Interferon-gamma