TOXICITY OF RECOMBINANT HUMAN INTERLEUKIN-2 IN RATS FOLLOWING INTRAVENOUS-INFUSION

Abstract

The recent availability of recombinant human interleukin-2 (RIL-2) has increased interest in the potential clinical use of this lymphokine. The biologic effects of intermittent bolus and continuous i.v. administration of RIL-2 in rats were examined. The mean (.+-. SEM [standard error of the mean]) half-life after an i.v. bolus injection of RIL-2 was determined to be 2.9 .+-. 0.5 min (n = 4). The administration of intermittent i.v. bolus injections of RIL-2 of doses up to 106 U/kg every other day for 2 wk was well tolerated without toxicity as determined by organ histology and serum chemistries. The continuous intravenous infusion of RIL-2 through an indwelling external jugular vein catheter was tolerated for 2 wk at doses .ltoreq. 3,000 U/kg per h and was associated with no abnormal serum chemistries or organ pathology. Animals that received > 10,000 U/kg per h demonstrated RIL-2 toxicity leading to death of treated rats. Serum chemistries revealed a 4-fold increase in serum glutamate oxaloacetic transaminase and serum glutamate pyruvic transaminase. Liver histology revealed hepatocellular necrosis with mononuclear cell infiltration. The thymus was depleted of lymphocytes and lymphoid infiltrates were present in liver, spleen and lung. This is the 1st documentation of toxicity secondary to RIL-2 administration and suggests that hepatopathy may be the dose-limiting toxicity accompanying the administration of RIL-2.