In vivo retrovirus-mediated gene transfer to the liver of dogs results in transient expression and induction of a cytotoxic immune response

Gene transfer in regenerating dog liver using high-titer recombinant retrov iral vectors carrying the E. coli beta-galactosidase gene was studied, Supe rnatants containing amphotropic or gibbon ape pseudotyped recombinant retro viruses were infused into a peripheral vein in beagle dogs after partial he patectomy. The kinetics of liver regeneration were determined in the animal s and daily infusions were carried out for 4 or 5 days during the regenerat ion period. Up to 2.8% of hepatocytes were beta-galactosidase positive at t he end of the procedure. However, the number of positive cells declined rap idly and few positive hepatocytes were detected after 3 weeks, PCR demonstr ated the disappearance of the provirus, Histologically, inflammatory lesion s were observed in the transduced livers, Finally, we demonstrated the pres ence of a cytotoxic T lymphocyte immune response directed against beta-gala ctosidase-expressing cells, which could explain the disappearance of the tr ansgene, This work suggests that the efficiency of in vivo gene delivery us ing high-titer retroviral vectors directly infused into the circulation may be hampered by a cytotoxic immune response against the infected cells.