Induction of long-term liver allograft survival by delayed immunosuppression is dependent on interleukin-10

Abstract

Background: A transit increase of plasma IL-10 level was detected duringthe early phase after reperfusion in the patients with liver transplantation.However, the possible mechanism that regulates this transit upregulationof endogenous IL-10 and its potential role in ischemia/reperfusion injuryand immune response remains to be determined. Aim of Study: We aimedto explore the potential role of the transit upregulation of endogenous IL-10 in ischemia/reperfusion injury and long-term survival of liver grafts ina rat orthotopic liver transplantation model. Materials and Methods:Male DA (RT1a) and LEW (RT1l) rats were used as donors and recipients,respectively. Experimental groups included: 1) No treatment (isograft); 2)IL-10 neutralizing antibody (isograft); 3) No treatment (allograft); 4) IL-10 Ab (allograft); 5) FK506 1 mg/kg intramuscular injection (im), Days 0-7 (allograft); 6) FK506, Days 2-7 (allograft); 7) IL-10 Ab combined withFK506, Days 2-7 (allograft); 8) Low dose FK506 (0.1 mg/kg); 9) Low doseFK506 combined with IL-10 recombinant protein (allograft). Plasma levelsof IL-10 were detected by ELISA. Primary culture of tissue lymphocyteswas performed. Foxp3 mRNA and protein expression was determined.Flow cytometry was performed to detect IL-10 expression in tissuemacrophages. Results: Long-term survival was observed in isografts,allografts with FK506 treatment and with low dose FK506 combined withIL-10 protein. However, administration of IL-10 neutralizing antibodysignificantly reduced the long-term survival of isografts, and allograftswith FK506 treatment. Decreased plasma levels of IL-10 were found in thegroups receiving IL-10 Ab and FK506 treatment. Parallel to the destructionof liver graft histology, increased plasma levels of ALT and total bilirubinwere detected in the groups with the treatment of IL-10 Ab during the earlyphase after reperfusion. Administration of IL-10 Ab reduced the expressionof IL-10 in tissue macrophages, and at the same time, downregulated theexpression of Foxp3 in the primarily isolated lymphocytes. Conclusions:The transit upregulation of endogenous IL-10 in liver grafts played animportant role in prevention of ischemia/reperfusion injury and inductionof long-term allograft survival, probably through generation of T regulatorycells.