Flt-3 ligand synergizes with granulocyte colony-stimulating factor to increase neutrophil numbers and to mobilize peripheral blood stem cells with long-term repopulating potential.
Flt-3 ligand (FL) shares many features with stem cell factor (SCF), a widely documented cofactor for peripheral blood progenitor cell (PBPC) mobilization. We investigated the mobilization of PBPCs by FL in combination with granulocyte colony-stimulating factor (G-CSF). As a single agent, FL was a relatively modest mobilizer of PBPCs, resulting in 360 granulocyte/macrophage colony-forming cells (GM-CFCs)/mL blood (control, 155 GM-CFCs/mL blood) and no advantage in leukocyte recovery when these PBPCs were transplanted to irradiated recipient mice. G-CSF, on the other hand, mobilized over 20,000 GM-CFCs/mL blood, and the combination of G-CSF + FL resulted in over 100,000 GM-CFCs/mL blood. The combination of G-CSF + FL stimulated increased levels of monocytes and basophils in the peripheral blood. The performance of the mobilized PBPC product in irradiated hosts correlated with progenitor numbers resulting in long-term engraftment in association with accelerated short-term recovery of both leukocytes and platelets. These data demonstrate the potential of FL to synergize with G-CSF to mobilize PBPCs with both short- and long-term engraftment potential. The effect is similar to the synergistic interaction of G-CSF and SCF on PBPC mobilization. The use of FL as opposed to SCF may elicit a different spectrum of toxicities including lymphoid proliferation effects, in contrast to the mast cell degranulation effects of SCF. Clinical studies of FL are needed to evaluate its usefulness in man.
Molineux
G
G
Department of Developmental Hematology, Amgen Inc, Thousand Oaks, CA 91320, USA.
McCrea
C
C
Yan
X Q
XQ
Kerzic
P
P
McNiece
I
I
D000818:Animals; D002469:Cell Separation; D004357:Drug Synergism; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000473:pathology*; D008565:Membrane Proteins / Q000494:pharmacology*; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000473:pathology*
D008565:Membrane Proteins; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor