Toxicity of recombinant human interleukin-2 in rats following intravenous infusion

The recent availability of recombinant human interleukin-2 (RIL-2) has increased interest in the potential clinical use of this lymphokine. We have examined the biologic effects of intermittent bolus and continuous intravenous administration of RIL-2 in rats. The mean (+/- SEM) half-life after an intravenous bolus injection of RIL-2 was determined to be 2.9 +/- 0.5 min (n = 4). The administration of intermittent intravenous bolus injections of RIL-2 of doses up to 10(6) units/kg every other day for 2 weeks 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 weeks at doses less than or equal to 3,000 U/kg/h and was associated with no abnormal serum chemistries or organ pathology. By contrast, animals that received less than 10,000 U/kg/h demonstrated RIL-2 toxicity leading to death of treated rats. Serum chemistries revealed a fourfold 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 first documentation of toxicity secondary to RIL-2 administration and suggests that hepatopathy may be the dose-limiting toxicity accompanying the administration of RIL-2.