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

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.