Different procarcinogenic potentials of lymphocyte subsets in a transgenic mouse model of chronic hepatitis B.
The immune response to hepatitis viruses is believed to be involved in the development of chronic hepatitis; however, its pathogenetic potential has not been clearly defined. The current study, using a transgenic mouse model of chronic hepatitis B, was designed to determine the relative contributions of the immune cell subsets to the progression of liver disease that induces hepatocellular carcinogenesis. Hepatitis B virus transgenic mice were adoptively transferred with CD4+ and CD8+ T cell-enriched or -depleted and B cell-depleted splenocytes obtained from hepatitis B surface antigen-primed, syngeneic nontransgenic donors. The resultant liver disease, hepatocyte apoptosis, regeneration, and tumor development were assessed and compared with the manifestations in mice that had received unfractionated spleen cells. Transfer of CD8(+)-enriched splenocytes caused prolonged disease kinetics, and a marked increase in the extent of hepatocyte apoptosis and regeneration. In 12 of 14 mice the transfer resulted in multiple hepatocellular carcinomas (HCCs) comparable with the manifestations seen in the mice transferred with total splenocytes. In contrast, mice that had received CD4(+)-enriched cells demonstrated lower levels of liver disease and developed fewer incidences of HCC (4 of 17). The experiment also revealed that all of the groups of mice complicated with HCC developed comparable mean numbers and sizes of tumors. B-cell depletion had no effect on disease kinetics in this model. Taken together, these results demonstrate that the pathogenetic events induced by CD8+ T-cell subset are primarily responsible for the induction of chronic liver disease that increases tumor incidence, suggesting their potential in triggering the process of hepatocarcinogenesis.
Nakamoto
Yasunari
Y
Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan.
Suda
Takashi
T
Momoi
Takashi
T
Kaneko
Shuichi
S
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D018450:Disease Progression; D006514:Hepatitis B Surface Antigens / Q000235:genetics / Q000276:immunology; D019694:Hepatitis B, Chronic / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology; D008114:Liver Neoplasms, Experimental / Q000276:immunology* / Q000821:virology; D008115:Liver Regeneration; D018655:Lymphocyte Count; D016131:Lymphocyte Subsets / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D013601:T-Lymphocytes / Q000276:immunology
D006514:Hepatitis B Surface Antigens