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Interactions of Erythropoietin, Granulocyte Colony-Stimulating
Factor, Stem Cell Factor, and Interleukin-11 on Murine
Hematopoiesis During Simultaneous Administration
I. Roeder,
G. de Haan,
C. Engel,
W. Nijhof,
B. Dontje, and
M. Loeffler
From the Institute for Medical Informatics, Statistics and
Epidemiology, University of Leipzig, Leipzig, Germany; the Division of
Hematology/Oncology, University of Kentucky Medical Center, Lexington,
KY; and the Groningen Institute for Drug Studies, University of
Groningen, Groningen, The Netherlands.
We investigated how in vivo effects of single hematopoietic
cytokines change if given in combination for a prolonged time. Mice
were treated with every combination of recombinant human (rh)
erythropoietin (EPO), rh granulocyte colony-stimulating factor (G-CSF),
recombinant rat (rr) stem cell factor (SCF), and rh interleukin (IL)-11 by continuous infusion over 7 days (full factorial
design with three dose levels for each cytokine). Burst-forming
unit-erythroid (BFU-E), colony-forming unit-erythroid (CFU-E), and
colony-forming unit-granulocyte-macrophage (CFU-GM) were determined in
bone marrow and spleen, reticulocytes, hematocrit, granulocytes, and
thrombocytes in the peripheral blood. An analysis of variance (ANOVA)
and multiple comparison of means was used to evaluate the data. For
several cell types, cytokine effects superimposed in an additive way if combined. However, in a large number of circumstances, nonadditive pairwise interactions were found. They differed in type and magnitude involving high-dose saturation, high-dose antagonistic effects, and
even effect reversals (qualitative interactions). Hence, in general, it
was not possible to foresee the combination effects on the basis of
existing knowledge of single effects. On the other hand, the cytokine
network was robust and no system hazards were observed under multiple
cytokine combinations. The results illustrate that the cytokine network
has nonlinear dynamic properties in vivo with dose-response
characteristics of one cytokine being continuously modified by other
cytokines.
Blood, Vol. 91 No. 9 (May 1), 1998:
pp. 3222-3229
© 1998 by The American Society of Hematology.
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