Prolonged survival of rat liver allografts transfected with Fas ligand-expressing plasmid

Background, Transplantation of Fas ligand (FasL) gene-transfected tissues c an have opposite effects. For example, cotransplantation of pancreas islets with myoblasts transfected with Fast-expressing plasmid vector (pFasL) pre vented graft rejection, whereas the expression of Fast directly within isle ts using adenovirus vector led to graft destruction, It was also reported t hat Fast expression on pancreas islets led to neutrophilic infiltration and rapid destruction of the islets. From these results, overexpression of Fas t in transfected tissues may lead directly to self destruction through an a utocrine Fas-Fast pathway or graft destruction through neutrophil recruitme nt. To date there have been no reports of successful transplantation of Fas t gene-transfected solid organs. Methods. Rat pFasL was transfected at a dose of 90, 180,270, or 360 mu g in to rat liver with an inactivated hemagglutinating virus of Japan conjugated to liposome vesicles (HVJ-liposome), and the gene-transfected livers were transplanted to allogeneic rats. Results. In 18 rats transfected with 180 mu g of pFasL, 14 (78%) did not de velop fulminant hepatitis. FasL-mRNA was detected in these livers at 3, 5, 7, and 14 days after transfection. The expression of FasL protein was also observed in the transfected liver, and the transfection rate by this method was 11.1+/-1.9%, The livers were then transplanted to allogeneic recipient s, resulting in significant (P<0.01) prolonged recipient survival times. Hi stological observation showed that the pFasL-transfected liver allografts c aused apoptotic cell death in infiltrating activated T cells. In contrast, transfection of pFasL higher than 180 mu g resulted in lethal hepatitis in all rats, and its low dose (90 mu g) did not induce the hepatitis or prolon g recipient survival. Conclusion. Our results indicate that rat Liver allografts can be protected to host immune responses by an adequate level (approximately 10%) of FasL expression in the livers using HVJ-liposome incorporating pFasL.