Preclinical safety studies with recombinant human interleukin 6 (rhIL-6) in the primate Callithrix jacchus (marmoset): comparison with studies in rats.
The haemopoietic and immunostimulatory properties of recombinant human interleukin 6 (rhIL-6) might be used clinically in cancer patients. For the preclinical assessment of the safety of such a therapy, we chose the primate marmoset (Callithrix jacchus) and Wistar rats. Recombinant hIL-6 given to marmosets at doses of up to 1000 micrograms kg-1 day-1 over 4 and 9 weeks did not induce fever and was very well tolerated. Haematological alterations included a sustained two- to threefold increase of thrombocyte counts, peaking at 4 weeks, as well as an increase in neutrophils and basophils. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased, but the ploidy grade was augmented. An acute-phase protein response was observed within 24 h after the first IL-6 administration, which reached a maximum after 1 week. The acute-phase protein response was not accompanied by functional or morphological signs of hepatocellular damage. Increased immunoglobulin and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. Recombinant hIL-6 was also given to rats at 500 micrograms kg-1 day-1 s.c. for 4 weeks, where it induced a stimulation of thrombopoiesis associated with increased platelet counts within 1 week. Furthermore, rhIL-6-treated rats had signs of immunostimulation and increased acute-phase reactants in serum, as in marmosets. There was no evidence of renal glomerular or hepatic pathology.(ABSTRACT TRUNCATED AT 250 WORDS)
Ryffel
B
B
University of Zurich, Institute of Toxicology, Switzerland.
Weber
M
M
D000209:Acute-Phase Proteins / Q000378:metabolism; D000818:Animals; D001491:Basophils / Q000166:cytology / Q000187:drug effects; D001682:Biological Availability; D001772:Blood Cell Count / Q000187:drug effects; D001792:Blood Platelets / Q000166:cytology / Q000187:drug effects*; D001853:Bone Marrow / Q000187:drug effects*; D001854:Bone Marrow Cells; D002144:Callithrix; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007107:Immune System / Q000187:drug effects*; D007136:Immunoglobulins / Q000378:metabolism; D007279:Injections, Subcutaneous; D015850:Interleukin-6 / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000502:physiology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000187:drug effects; D008297:Male; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015375:Receptors, Interleukin-2 / Q000187:drug effects / Q000378:metabolism; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity
D000209:Acute-Phase Proteins; D007136:Immunoglobulins; D015850:Interleukin-6; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins