Effects of intrahepatic arterial and intraportal administration of FK 506 on liver allograft survival in rats.

Abstract

Rejection is still the limiting factor for successful organ transplantation, and overdosage of immunosuppressive drugs often results in severe viral infection, side-effects and toxicity. Thus, more specific immunosuppression to lessen these side-effects is highly desirable. In this study, we compared the effects of FK 506 administered by different routes (hepatic artery, portal vein and systemic circulation) on the inhibition of rejection. FK 506 was given to recipient LEW rats with PVG liver grafts via the penile vein (systemic administration), portal vein or hepatic artery (local administration) for 3 or 7 successive days after liver transplantation. In control LEW rats without immunosuppression, the PVG liver allografts were rejected between 9 and 21 days after transplantation. Intravenous administration of FK 506 for 3 days (0.32 and 1.28 mg/kg daily) only had a marginal effect on prolonging liver allograft survival (21.1 +/- 12.5 and 32.0 +/- 24.0 days, respectively; control 14.1 +/- 4.1 days). However, systemic administration of FK 506 (0.08-1.28 mg/kg daily) for 7 days suppressed liver allograft rejection markedly (42.3 +/- 5.9 to 80.5 +/- 53.4 days; control 14.1 +/- 4.1 days), and 50% of the recipient rats survived for at least 60 days after liver transplantation. Moreover, when a low dose of FK 506 (0.32 mg/kg) was infused into the hepatic artery or portal vein of the transplanted liver for 3 days only, liver allograft survival times were prolonged markedly, and 54% of rats with grafts survived for at least 60 days. This effect was almost equal to that after 7 days systemic treatment with FK 506. In conclusion, 7 days' treatment with FK 506 administered systemically was an effective regimen for the suppression of liver allograft rejection in rats. Furthermore, local immunosuppression with low-dose, short-term (3 days) FK 506 treatment administered via the hepatic artery or portal vein of the transplanted liver dramatically improved allograft salvage.