Role of asialo-GM1-positive lymphoid cells in mediating the toxic effects of recombinant IL-2 in mice.
Studies were performed to characterize the toxic effects of human rIL-2 in mice and to examine the mechanism of toxicity. Intraperitoneal administration of rIL-2 at doses greater than or equal to 2 X 10(6) U/kg twice each day for greater than or equal to 4 days led to toxicity in several strains of mice. The toxic effects of rIL-2 included the vascular leak syndrome (manifested by pulmonary edema, pleural effusions, and ascites), elevated hepatic transaminases, hyperbilirubinemia, hypoalbuminemia, pre-renal azotemia, anemia, thrombocytopenia, mild eosinophilia, and death. Marked lymphoid cell infiltration of pulmonary and hepatic vasculature was present in mice suffering from rIL-2 toxicity, and the pleural and ascitic fluids also contained high numbers of mononuclear cells. Mononuclear cells isolated from the pleural fluids and livers of these mice were 74 to 98% Thy-1+, 55 to 83% asialo-GM1+, 29 to 45% Lyt-2+, and less than 10% L3T4+. These cells possessed potent lymphokine-activated killer (LAK)-like activity in that their ability to lyse cells of the NK-resistant P815 mastocytoma line was 10- to 100-fold higher on a per cell basis than splenocytes from the same animals. A correlation was found between the dose level, duration, and frequency of dosing with rIL-2 required to induce pleural effusions and hepatotoxicity and the dosage regimens required to produce the LAK-like cells in the pleural cavities and livers, respectively, of rIL-2-treated mice. Moreover, treatment of mice with anti-asialo-GM1 (anti-ASGM-1) antiserum in vivo at the same time they were receiving toxic doses of rIL-2 abolished or greatly reduced the severity of the vascular leak syndrome and hepatotoxicity and significantly prolonged the survival of the mice. Administration of anti-ASGM-1 to mice receiving toxic doses of rIL-2 resulted in a marked reduction in the LAK-like cytolytic activity of their pleural and liver lymphoid cells and a corresponding reduction in the percentage of ASGM-1+ cells in pulmonary and hepatic lymphoid infiltrates. Nevertheless, the overall extent of pulmonary and hepatic lymphoid infiltration, as well as other consequences of rIL-2 administration, including splenomegaly, hypoalbuminemia, eosinophilia, and thrombocytopenia, were not diminished as a result of anti-ASGM-1 treatment.(ABSTRACT TRUNCATED AT 400 WORDS)
Gately
M K
MK
Department of Immunopharmacology, Hoffmann-La Roche, Inc., Nutley, NJ 07110.
Anderson
T D
TD
Hayes
T J
TJ
D000818:Animals; D005677:G(M1) Ganglioside; D006028:Glycosphingolipids / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000633:toxicity*; D007694:Killer Cells, Natural / Q000145:classification* / Q000276:immunology; D008099:Liver / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D010641:Phenotype; D011994:Recombinant Proteins / Q000633:toxicity*; D013577:Syndrome; D014652:Vascular Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology
D006028:Glycosphingolipids; D007376:Interleukin-2; D011994:Recombinant Proteins; D005677:G(M1) Ganglioside; C018835:asialo GM1 ganglioside