M Kammüller | PubMed Health

PubMed1997

Extrapolation of experimental safety data to humans: the interleukin-6 case.

Interleukin 6 (IL-6) has a broad spectrum of biological activities, which include stimulation of hemopoiesis, especially thrombopoiesis, of the immune response, proliferation of mesangium cells, and induction of acute-phase proteins in the liver. Therefore, the therapeutic use of IL-6 for any specific clinical indication, e.g., stimulation of thrombopoiesis in severe thrombocytopenia, may be complicated by nonspecific effects. Preclinical experimental investigations of the safety evaluation performed in primates and rodents showed that rhIL-6 is well tolerated. A two- to three-fold increase in thrombocyte counts was observed along with an increase in acute-phase proteins and immunostimulation in the absence of target organ toxicity. Patients receiving rhIL-6, however, had a vigorous acute-phase response, with fever, anemia, and general malaise. Importantly, rhIL-6 administration did not cause mesangioproliferative nephritis or an uncontrolled lymphoproliferation as predicted from IL-6 transgenic mice. Although preclinical investigations are in general quite predictive for humans, safety data should be extrapolated carefully, since important quantitative differences may occur.

Animals↗

PubMed1994

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

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.

Acute-Phase Proteins↗

PubMed1992

Pathology induced by interleukin-6.

Interleukin 6 (IL-6) is a multi-functional cytokine which plays an important role in the immune response, hemopoiesis and host defense. Recombinant human IL-6 (rhIL-6) was administered at high doses to mice, rats and non-human primates. In all species IL-6 had an immunostimulatory and hemopoietic (especially on megakaryocytes) effect. An acute phase response was most pronounced in non-human primates, which was not, however, associated with any major histopathological liver change. Finally, no evidence of glomerular pathology was found. Neutralising antibodies were detected within 10 days of rhIL-6 administration in all species.

Animals↗