Tumor necrosis factor-induced hepatic DNA fragmentation as an early marker of T cell-dependent liver injury in mice.
OBJECTIVE
The injection of mice with anti-CD3 monoclonal antibody causes activation of T lymphocytes and leads to a lethal shock syndrome. The aim of this study was to investigate T cell-dependent, cytokine-mediated target cell death that leads to organ injury.


METHODS
Anti-CD3 monoclonal antibody or staphylococcal enterotoxin B was injected into mice sensitized by D-galactosamine. Liver injury was assessed biochemically and histologically, and circulating cytokines were determined.


RESULTS
Mice sensitized with D-galactosamine developed severe liver injury within 8 hours after injection of anti-CD3 monoclonal antibody or staphylococcal enterotoxin B. Apoptotic bodies and chromatin condensation were detectable 5 hours after anti-CD3 monoclonal antibody challenge. DNA fragmentation in the liver preceded the increase in plasma alanine aminotransferase activity. Anti-CD3 monoclonal antibody induced the release of tumor necrosis factor and other cytokines. Passive immunization against tumor necrosis factor or pretreatment with immunosuppressive drugs protected mice from liver injury. Liver injury associated with apoptotic cell death and DNA fragmentation was also noted in D-galactosamine-sensitized mice injected with staphylococcal enterotoxin B.


CONCLUSIONS
Tumor necrosis factor-induced hepatic apoptosis followed by necrosis may represent a general pathomechanism of T-cell shock models using D-galactosamine-sensitized mice.
Gantner
F
F
Faculty of Biology, University of Konstanz, Germany.
Leist
M
M
Jilg
S
S
Germann
P G
PG
Freudenberg
M A
MA
Tiegs
G
G
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D004249:DNA Damage; D004768:Enterotoxins / Q000494:pharmacology; D005688:Galactosamine / Q000276:immunology; D007114:Immunization; D008099:Liver / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D017093:Liver Failure / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D012769:Shock / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D004768:Enterotoxins; D014409:Tumor Necrosis Factor-alpha; C031818:enterotoxin B, staphylococcal; D005688:Galactosamine; D000410:Alanine Transaminase