Takashi Omura

Prolongation of canine liver allograft survival by a novel immunosuppressant, FTY720. Effect of monotherapy and combined treatment with conventional drugs

BACKGROUND The immunosuppressive effect and other properties of a novel immunosuppressant, FTY720, have been studied mostly in the experimental transplantation of various extrahepatic organs. In this experiment, we evaluated the antirejection potency and adverse effects of this agent on liver grafts using a canine liver transplantation model. METHODS Forty-eight orthotopic liver transplantations were performed by the standard technique under a veno-venous bypass. Liver recipients were divided into two studies: a single-dose study with FTY720 at various doses and a combined dose study with conventional immunosuppressants (cyclosporine or tacrolimus) alone and combined with FTY720. Survival, biochemical and hematological tests, blood levels of immunosuppressants, and postmortem histology were determined. RESULTS The median survival of untreated control animals was 9 days, whereas treatment with FTY720 at a dose of 0.1 mg/kg/day prolonged graft survival to 49.5 days. FTY720 at 1 mg/kg/day showed a slight but insignificant prolongation to 16 days, but when the dose was increased to 5 mg/kg/day, the graft was rejected at 10 days. The combination of FTY720, 0.1 mg/kg/day, with a subtherapeutic dose of cyclosporine, 5 mg/kg/ day, prolonged median animal survival from 40 days with cyclosporine alone to 74 days. A combination of FTY720 (0.1 mg/kg/day) with tacrolimus (0.5 mg/kg/ day) compromised animal survival, reducing survival from 83.5 days with tacrolimus alone to 30.5 days due to infectious complication and emaciation by overimmunosuppression. No evident drug-induced side effects were observed. CONCLUSIONS FTY720 has a potent immunosuppressive effect when used alone at 0.1 mg/kg/day in canine liver transplantation. FTY720 is a promising candidate for future clinical application in orthotopic liver transplantation.

Fifty-percent partial liver transplantation in the rat

Reduced-size liver transplantation in the rat has been useful in the study of hepatic regeneration. We describe a modified technique for partial liver transplantation in the rat using a 50% reduced-size graft. Male Lewis rats (RT1(1)), weighing 250 to 280 g, were used as donors and recipients. The harvested donor liver was placed in 4 degrees C cold saline and graft reduction was performed ex situ by resecting the left lateral lobe, the left portion of the median lobe, and the caudate lobes. The reduced graft was composed of the right portion of the median lobe and the right lobe, weighing 5.33 +/- O.58 g (53.6 +/- 2.2% of the donor liver before reduction, n=7). The recipient 1-week survival rate was 85.7%. The use of reduced livers permits the study of host responses to a deficient graft. This technique provides another choice of liver volume to be implanted and allows the study of regeneration of small-for-size livers more precisely in combination with more extensive graft reduction.