Toxicity of human recombinant interleukin-2 in rats. Pathologic changes are characterized by marked lymphocytic and eosinophilic proliferation and multisystem involvement.
To characterize the subacute toxicologic and pathologic effects of human recombinant interleukin-2 (rIL-2) in rats, rIL-2 was administered to rats at doses ranging from 3.0 to 150 X 10(6) units/kg/day for 14 to 16 days, in once or twice daily dosing regimens by intravenous or intraperitoneal dosing routes. The hematologic, clinical chemical, gross pathologic and histopathologic findings were determined. Rats given rIL-2 had dose- and regimen-related incidences of hemolytic anemia, lymphocytosis, neutrophilia, eosinophilia, thrombocytopenia, increased hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, ascites and pleural effusions, and prerenal azotemia. Marked lymphoid infiltration of the liver and eye were associated with hepatocyte necrosis and retinal damage. Eosinophilic infiltration of the adrenal medulla was associated with medullary cell necrosis. Other histopathologic changes included infiltration of multiple tissues by eosinophils and/or lymphocytes, lymphoid hyperplasia and splenic extramedullary erythropoiesis and eosinopoiesis. Hematologic, clinical chemistry, and histopathologic changes were of markedly greater severity in rats receiving rIL-2 twice daily as compared with those receiving the same total dose of rIL-2 once daily. Mortality in severely affected rats was secondary to severe anemia and/or hepatic damage. The results of these studies demonstrate that the major pathologic changes associated with rIL-2 administration in rats are characterized by marked tissue infiltration with lymphocytes and eosinophils. Many of the adverse effects of rIL-2 administration to rats are similar to those reported in humans receiving rIL-2 immunotherapy and the results confirm that the rat is an appropriate species in which to study selected aspects of rIL-2 toxicity.
Anderson
T D
TD
Department of Toxicology and Pathology, Hoffmann-La Roche, Nutley, New Jersey.
Hayes
T J
TJ
D000313:Adrenal Medulla / Q000473:pathology; D000740:Anemia / Q000209:etiology*; D000818:Animals; D004802:Eosinophilia / Q000209:etiology*; D005123:Eye / Q000187:drug effects / Q000473:pathology; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000633:toxicity*; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D008168:Lung / Q000473:pathology; D008213:Lymphocyte Activation; D008297:Male; D009929:Organ Size; D010902:Pituitary Gland / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000633:toxicity; D013154:Spleen / Q000473:pathology; D013950:Thymus Gland / Q000473:pathology
D007376:Interleukin-2; D011994:Recombinant Proteins