Reduction of FK-506 requirements by combination with polyethylene glycol superoxide dismutase in orthotopic rat liver transplantation.
Reperfusion after ischemia results in endothelial cell injury and Kupffer cell activation. Inflammatory cytokines thus released can induce major histocompatibility complex antigens and increase the immunogenecity of the graft. An orthotopic rat liver allotransplant model was used to test the hypothesis that prevention of reperfusion injury by infusion of polyethylene glycol superoxide dismutase (PEG-SOD) would result in long-term allograft survival in the presence of subthreshold immunosuppressive dosages. ACI rats were used as donors, and Lewis strain rats as recipients. Orthotopic liver transplantation was initially performed to identify a subthreshold dose of the immunosuppressant FK-506, which would be unable to extend survival longer than control untreated rats with this strain combination. After testing three intramuscular FK-506 doses of 0.04, 0.08, and 0.16 mg/kg, it was observed that an FK-506 dose of 0.04 mg/kg/day for 14 days was unable to extend survival longer than in untreated recipients. This dose of FK-506 was used in combination with PEG-SOD at doses of 1000, 3000, 10,000, or 30,000 units. Recipient animals were treated intravenously with PEG-SOD as a loading dose to facilitate tissue penetration on day 1, and beginning on the day of transplantation, every 2 days for the duration of the study. Results of histologic studies and mean survival time were compared in untreated recipients and in rats treated with PEG-SOD plus 0.04 mg/kg/day FK-506.(ABSTRACT TRUNCATED AT 250 WORDS)
Rao
P N
PN
Department of Surgery, University of Pittsburgh, PA, USA.
Cai
X
X
Venkataramanan
R
R
Platt
J L
JL
Demetris
A
A
Thunberg
A
A
Faltynek
C
C
Starzl
T
T
Kumar
P
P
D000818:Animals; D004347:Drug Interactions; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival; D008099:Liver / Q000473:pathology; D016031:Liver Transplantation; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D051381:Rats; D011912:Rats, Inbred ACI; D011917:Rats, Inbred Lew; D015427:Reperfusion Injury / Q000517:prevention & control*; D013482:Superoxide Dismutase / Q000008:administration & dosage*; D016559:Tacrolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics; D014184:Transplantation, Homologous
D011092:Polyethylene Glycols; D013482:Superoxide Dismutase; C063471:polyethylene glycol-superoxide dismutase; D016559:Tacrolimus