Inhibition of Fas-mediated fulminant hepatitis in CrmA gene-transfected mice

Hyperimmune response via Fas/Fas-ligand and perforin/granzyme pathways may be essential in pathogenesis of virus-induced fulminant hepatitis. CrmA inh ibits activation of caspases and granzyme B, suggesting it may block these pathways. We investigated whether CrmA expression would inhibit Fas-associa ted lethal hepatitis in mice, We successfully generated AxCALNLCrmA, a reco mbinant adenovirus expressing CrmA gene with a Cre-mediated switching casse tte. We increased CrmA expression level in the liver transfected with AxCAL NLCrmA (10(9) pfu) by increasing administration dose (10(7)-10(9) pfu) of A xCANCre, a recombinant, adenovirus-expressing Cre gene. injection of anti-F as antibody into the control mice rapidly led to animal death due to massiv e liver apoptosis, while the apoptosis was dramatically reduced in the CrmA -expressed mice. The animal survival increased with an increase of CrmA exp ression. The formation of active caspase-3 was markedly inhibited in the cr mA-transfected hepatocytes in vitro. These results suggest that crmA is an effective gene that can inhibit immune-related liver apoptosis. (C) 2000 Ac ademic Press.