MUTUAL INHIBITION OF MURINE ERYTHROPOIESIS AND GRANULOPOIESIS DURING COMBINED ERYTHROPOIETIN, GRANULOCYTE-COLONY-STIMULATING FACTOR, AND STEM-CELL FACTOR ADMINISTRATION - IN-VIVO INTERACTIONS AND DOSE-RESPONSESURFACES
G. Dehaan et al., MUTUAL INHIBITION OF MURINE ERYTHROPOIESIS AND GRANULOPOIESIS DURING COMBINED ERYTHROPOIETIN, GRANULOCYTE-COLONY-STIMULATING FACTOR, AND STEM-CELL FACTOR ADMINISTRATION - IN-VIVO INTERACTIONS AND DOSE-RESPONSESURFACES, Blood, 84(12), 1994, pp. 4157-4163
We investigated the in vivo effects of erythropoietin (EPO) on granulo
poiesis and, conversely, the effect of granulocyte colony-stimulating
factor (G-CSF) treatment on erythropoiesis. Recombinant human EPO at f
our different doses in combination with recombinant human G-CSF also a
t four different doses was simultaneously administered for 7 days to s
plenectomized mice. In total, 16 different combinations of growth fact
ors were thus tested. G-CSF administration increased granulocyte produ
ction as expected, whereas immature colony-forming unit granulocyte-ma
crophage numbers were decreased. EPO analogously increased late erythr
oid cell numbers. Both EPO and G-CSF dose-dependently inhibited late c
ell stages of the opposite lineage, with EPO abrogating G-CSF-stimulat
ed granulopoiesis and, conversely, G-CSF inhibiting EPO-stimulated ery
thropoiesis. In a subsequent experiment, we tested whether these linea
ge-competitive effects could be prevented by coadministering stem cell
factor (SCF). In these three factor-treated mice, all granuloid and e
rythroid cell stages increased, thereby reducing the effect of the mut
ual inhibition. We conclude that EPO-stimulated erythropoiesis and G-C
SF-stimulated granulopoiesis inhibited each other at a late level, Sim
ultaneous SCF administration increased the input into both the erythro
id and granuloid compartment and thereby compensated the mutual inhibi
tion. This study shows that intricate dose-response relationships exis
t between various growth factors that should be carefully analyzed bef
ore combinations of these factors are used in humans. (C) 1994 by The
American Society of Hematology.