PROLONGED SURVIVAL OF RAT LIVER ALLOGRAFTS TRANSFECTED WITH FAS LIGAND-EXPRESSING PLASMID1

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Abstract
Transplantation of Fas ligand (FasL) gene-transfected tissues can have opposite effects. For example, cotransplantation of pancreas islets with myoblasts transfected with FasL-expressing plasmid vector (pFasL) prevented graft rejection, whereas the expression of FasL directly within islets using adenovirus vector led to graft destruction. It was also reported that FasL expression on pancreas islets led to neutrophilic infiltration and rapid destruction of the islets. From these results, overexpression of FasL in transfected tissues may lead directly to self destruction through an autocrine Fas-FasL pathway or graft destruction through neutrophil recruitment. To date there have been no reports of successful transplantation of FasL gene-transfected solid organs. Rat pFasL was transfected at a dose of 90, 180, 270, or 360 µg into 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. In 18 rats transfected with 180 µg of pFasL, 14 (78%) did not develop 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 recipients, resulting in significant (P < 0.01) prolonged recipient survival times. Histological observation showed that the pFasL-transfected liver allografts caused apoptotic cell death in infiltrating activated T cells. In contrast, transfection of pFasL higher than 180 µg resulted in lethal hepatitis in all rats, and its low dose (90 µg) did not induce the hepatitis or prolong recipient survival. 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.