|
|
 Previous Article | Table of Contents | Next Article 
Long-term interleukin-6 administration stimulates sustained thrombopoiesis
and acute-phase protein synthesis in a small primate-- the marmoset
B Ryffel, BD Car, G Woerly, M Weber, F DiPadova, M Kammuller, S Klug, R Neubert and D Neubert
University of Zurich, Institute of Toxicology, Schwerzenbach, Switzerland.
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.
Volume 83,
Issue 8,
pp. 2093-2102,
04/15/1994
Copyright © 1994 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
V. Seshadri, P. L. Fox, and C. K. Mukhopadhyay
Dual Role of Insulin in Transcriptional Regulation of the Acute Phase Reactant Ceruloplasmin
J. Biol. Chem.,
July 26, 2002;
277(31):
27903 - 27911.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
F. Bracho, M. D. Krailo, V. Shen, S. Bergeron, V. Davenport, W. Liu-Mares, B. R. Blazar, A. Panoskaltsis-Mortari, C. van de Ven, R. Secola, et al.
A Phase I Clinical, Pharmacological, and Biological Trial of Interleukin 6 Plus Granulocyte-Colony Stimulating Factor after Ifosfamide, Carboplatin, and Etoposide in Children with Recurrent/Refractory Solid Tumors: Enhanced Hematological Responses but a High Incidence of Grade III/IV Constitutional Toxicities
Clin. Cancer Res.,
January 1, 2001;
7(1):
58 - 67.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
H. Hibino, K. Tani, K. Ikebuchi, M.-S. Wu, H. Sugiyama, Y. Nakazaki, T. Tanabe, S. Takahashi, A. Tojo, S. Suzuki, et al.
The Common Marmoset as a Target Preclinical Primate Model for Cytokine and Gene Therapy Studies
Blood,
May 1, 1999;
93(9):
2839 - 2848.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Isobe, T. Kanda, H. Sakamoto, Y. Morishita, T. Suzuki, and I. Kobayashi
Myocardial Infarction in Myxoma Patients with Normal Coronary Arteries: Case Reports
Angiology,
August 1, 1996;
47(8):
819 - 823.
[Abstract]
[PDF]
|
|
|
|
|
