Effects of recombinant human interleukin 6 (rhIL-6) in marmosets (Callithrix jacchus). 1. General toxicity and hematological changes.
The physiological and toxicological properties of recombinant human interleukin 6 (rhIL-6) were assessed in marmoset monkeys (Callithrix jacchus). Two experimental series were performed with daily subcutaneous administration: (a) 5 or 1000 micrograms rhIL-6/kg per day for three weeks and (b) 25, 100 or 500 micrograms rhIL-6/kg per day for 3 months. RhIL-6 was well tolerated and did not induce fever or any other non-specific signs of toxicity. The main findings were: (1) A two- to threefold increase in platelet counts at 2-4 weeks, which decreased following further continuous rhIL-6 administration; (2) increase in total white blood cells between 1 and 4 weeks of administration, including an absolute increase in granulocytes (including band forms) and basophils. A change in the number of monocytes was not detected; (3) an increase in total red blood cells, which peaked at 4 weeks, sustained elevation of red cell distribution width and a slight decrease in hemoglobin between week 1 and 4, concurrent with a distinct decrease in mean corpuscular hemoglobin at 4 weeks. This effect persisted for 9 weeks in the 100 micrograms/kg and 500 micrograms/kg groups; (4) decrease in plasma AST activity and increase in plasma protein concentration after 2 weeks of treatment; (5) no clinical or biochemical signs of renal glomerular dysfunction; (6) RhIL-6 after s.c. administration was detectable in the plasma, peak levels (mean values +/- SD) of 9.4 +/- 6.3 and 72.4 +/- 7.7 ng/ml were measured after a single dose of 100 or 1000 micrograms/kg; (7) antibodies against rhIL-6 developed within 2 weeks, increased during administration and neutralized the biological effect of rhIL-6 progressively from 4 to 9 weeks. In conclusion, aside from a mild anemia, rhIL-6 was well tolerated in marmosets and had a profound and sustained effect on thrombopoiesis. Due to the formation of neutralizing antibodies, the chronic biological effect of rhIL-6 is lost in marmosets and studies beyond 4 weeks are rendered less meaningful. The analyses of antibody formation, induction of acute phase proteins, histological changes and alterations on lymphocyte receptors will be reported in two following publications.
Universitätsklinikum Rudolf Virchow, Freie Universität Berlin, Germany.
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Klug
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Neubert
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Stahlmann
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Thiel
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Ryffel
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Car
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Neubert
D000704:Analysis of Variance; D000818:Animals; D000917:Antibody Formation; D001773:Blood Cells / Q000187:drug effects*; D001774:Blood Chemical Analysis; D001798:Blood Proteins / Q000187:drug effects / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002144:Callithrix; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D004912:Erythrocytes / Q000187:drug effects; D005260:Female; D006454:Hemoglobins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D007678:Kidney Glomerulus / Q000187:drug effects; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D010976:Platelet Count / Q000187:drug effects; D011897:Random Allocation; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity
D001798:Blood Proteins; D006454:Hemoglobins; D015850:Interleukin-6; D011994:Recombinant Proteins