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.
Klug
S
S
Universitätsklinikum Rudolf Virchow, Freie Universität Berlin, Germany.
Neubert
R
R
Stahlmann
R
R
Thiel
R
R
Ryffel
B
B
Car
B D
BD
Neubert
D
D
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