LOCAL IMMUNOSUPPRESSION WITH BUDESONIDE AFTER LIVER TRANSPLANTATION IN THE RAT

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Abstract
In this study we have analyzed the local immunosuppression with budesonide, a topically selective glucocorticosteroid, in rats after orthotopic liver transplantation. Because of its high first-pass hepatic clearance budesonide can be given orally, achieving high intrahepatic and low systemic concentrations.Using an acute rejection model from Dark Agouti (DA) to Lewis rats, the histomorphological degree of rejection was assessed on histological sections at the ninth postoperative day.Livers of the DA to Lewis study group without immunosuppression revealed severe allograft rejection with vast cellular infiltrates, massive endothelialitis, and hepatocyte necrosis. In the three budesonide study groups (250 microg, 500 microg, and 1 mg/kg/day) a moderate to mild liver allograft rejection was seen. Rejection was most prominent in the 250 microg group, whereas the 1 g group showed almost no signs of rejection, similar to the Lewis to Lewis control group. Aspartate and alanine transaminase (sGOT, sGPT) as well as alkaline phosphatase serum levels correlated with the degree of rejection, achieving highest levels in the DA to Lewis group without immunosuppression. Animals treated with 1 g of budesonide had serum levels similar to Lewis to Lewis control animals.These results implicate a beneficial effect of local immunosuppression with budesonide in rats based on the histomorphological degree of liver allograft rejection.