Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice.
OBJECTIVE
Priming immune responses against alpha-fetoprotein (AFP) highly expressed in the majority of hepatocellular carcinomas results in significant antitumoral T-cell responses. Liver regeneration in humans and mice, however, is also associated with increased AFP expression. Therefore, we evaluated the risk of AFP-directed immunotherapeutic approaches to induce autoimmunity against the regenerating liver.


METHODS
Mice were immunized with DNA encoding mouse AFP. For induction of liver regeneration, partial hepatectomy was performed and mice were monitored by serial histopathologic examinations and measurements of serum ALT activities (U/L), and by determination of the kinetics of AFP-specific T-cell responses.


RESULTS
Livers of AFP immune mice without partial hepatectomy were characterized by minor lymphocytic infiltrations without transaminase elevations. By contrast, a significant hepatocyte damage was observed in regenerating liver that correlated well with the number of AFP-specific CD8(+) T cells, the activity of liver regeneration, and the level of AFP synthesis. Autoimmune liver damage was mediated by CD4(+) T cell-dependent CD8(+) cytotoxic T lymphocytes.


CONCLUSIONS
These results show that priming of T-cell responses against shared tumor-specific self antigens may be accompanied by induction of autoimmunity dependent on the level of expression of the self antigen and have important implications for the development of antitumoral vaccines targeted against antigens that are not strictly tumor-specific.
Geissler
M
M
Department of Medicine II, University Hospital Freiburg, Freiburg, Germany. mgeissl@ukl.uni-freiburg.de
Mohr
L
L
Weth
R
R
Köhler
G
G
Grimm
C F
CF
Krohne
T U
TU
von Weizsäcker
F
F
Blum
H E
HE
D000818:Animals; D001327:Autoimmune Diseases / Q000209:etiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D006498:Hepatectomy; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D008107:Liver Diseases / Q000209:etiology* / Q000276:immunology; D008115:Liver Regeneration / Q000276:immunology*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D013601:T-Lymphocytes / Q000276:immunology*; D000509:alpha-Fetoproteins / Q000235:genetics / Q000276:immunology*
D000509:alpha-Fetoproteins