Long-term interleukin-6 administration stimulates sustained thrombopoiesis and acute-phase protein synthesis in a small primate : the Marmoset

• Published in: Blood 1994-04, Vol.83 (8), p.2093-2102
• Main Authors: RYFFEL, B, WOERKY, G, WEBER, M, DIPADOVA, F, KAMMÜLLER, M, KLUG, S, NEUBERT, R, NEUBERT, D
• Format: Article
• Language: English
• Subjects: Acute-Phase Proteins - biosynthesis; Animals; Biological and medical sciences; Blood Platelets - drug effects; Blood Platelets - physiology; Callithrix; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Female; Fundamental and applied biological sciences. Psychology; Hematopoiesis - drug effects; Immune System - drug effects; Interleukin-6 - immunology; Interleukin-6 - pharmacokinetics; Interleukin-6 - pharmacology; Kidney - drug effects; Kidney - pathology; Kidney - physiology; Liver - metabolism; Male; Molecular and cellular biology; Recombinant Proteins - pharmacology; Time Factors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.v83.8.2093.2093

Interleukin-6 (IL-6) has been ascribed significant roles in both hematopoiesis and the immune response, although its contribution to host defence as a whole is poorly understood. Because short-term IL-6 treatment was previously shown to stimulate megakaryocytopoiesis, we investigated the effect of long-term administration of IL-6 on megakaryocytopoiesis and other systemic parameters in nonhuman primates. We chose a small primate, the marmoset (Callithrix jacchus), which enabled long-term administration at high doses. Recombinant human IL-6 (rhIL-6) administered at doses of up to 1,000 micrograms/kg/d over 4 and 9 weeks caused a sustained twofold to threefold increase of thrombocyte counts, peaking at 4 weeks. Thrombocyte counts declined thereafter, despite continuing IL-6 administration. The number of bone marrow megakaryocytes at 4 and 9 weeks was not increased compared with controls, but the ploidy grade was augmented, suggesting that IL-6 effects are restricted to mature megakaryocytes in vivo. An acute-phase protein response was observed within 24 hours after the first IL-6 administration and reached a maximum after 1 week of IL-6 administration at 25 micrograms/kg. Serum C-reactive protein, haptoglobin, and ceruloplasmin were increased, whereas albumin and transferrin levels declined. The acute-phase protein response was not associated with any morphologic evidence of hepatocellular damage. The increased levels of Ig and soluble IL-2 receptor in the serum levels reflected systemic immunostimulation. There was no evidence of renal mesangioproliferative pathology. Antibodies against rhIL-6 developed within 2 weeks, continuously increasing during the course of the study. High titers of neutralizing antibodies appeared concomitantly with the decrease in platelet counts and decline in acute-phase proteins. Therefore, despite the pleiotropic effects of IL-6 observed in vitro, long-term administration of IL-6 caused a selective and sustained stimulation of thrombopoiesis in marmosets that was only ablated by the appearance of neutralizing antibodies, and high doses were well tolerated in marmosets. A long-term targeting of IL-6 to cells of the megakaryocytic lineage, without evoking general toxicity, confirms the potential therapeutic usefulness of rhIL-6 for the chronic treatment of thrombocytopenic patients.