Proteolytic enzyme levels are increased during granulocyte colony-stimulating factor-induced hematopoietic stem cell mobilization in human donors but do not predict the number of mobilized stem cells.
Previous studies from our laboratory indicate that functional, mature neutrophils are essential for interleukin-8 (IL-8)-induced stem cell mobilization. To study a possible role of neutrophils in granulocyte colony-stimulating factor (G-CSF) induced hematopoietic mobilization, we assessed the number of circulating CD34+ cells in healthy allogeneic stem cell donors on days 3, 4, and 5 of mobilization for comparison with the number of peripheral blood neutrophils and the plasma levels of IL-8, Flt3 ligand (FL), matrix metalloproteinase-9 (MMP-9), and human neutrophil elastase (HNE). Thirty-seven of 45 donors required 1 day of apheresis to obtain 5 x 10(6) CD34+/kg recipient body weight (high responders), the remaining 8 donors required 1 extra day of apheresis on day 6 (low responders). On day 5, CD34+ numbers in the blood were significantly highe in high responders (116 x 10(3) +/- 10.4/ml) than in low responders (54.1 x 10(3) +/- 10.3, p < 0.001). In all donors, MMP-9 and HNE levels were increased compared to nonmobilized individuals, but in high responders, plasma MMP-9 levels on days 3-5 of mobilization were substantially higher than in low responders (p < or = 0.02 for MMP-9 and p = 0.89, p = 0.05 and p = 0.52 for HNE on days 3, 4, and 5, respectively). These results are in accordance with the hypothesis that neutrophils play a role in G-CSF-induced mobilization through the release of proteases such as MMP-9 and elastase. No change in plasma levels of IL-8 or Flt3 ligand was observed, suggesting that these cytokines do not play a role in stem cell mobilization. However, because stem cell numbers could not be predicted by proteolytic enzyme levels and/or neutrophil numbers, other undefined factors may be more important.
Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
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R
van Os
M L J
ML
van Schie
R
R
Willemze
W E
WE
Fibbe
D018952:Antigens, CD34 / Q000032:analysis; D001772:Blood Cell Count; D001782:Blood Donors; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D010450:Endopeptidases / Q000097:blood* / Q000187:drug effects; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization / Q000592:standards*; D006801:Humans; D016209:Interleukin-8 / Q000097:blood; D007937:Leukapheresis; D019272:Leukocyte Elastase / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood; D008565:Membrane Proteins / Q000097:blood; D011994:Recombinant Proteins
D018952:Antigens, CD34; D016207:Cytokines; D016209:Interleukin-8; D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein; D016179:Granulocyte Colony-Stimulating Factor; D010450:Endopeptidases; D019272:Leukocyte Elastase; D020780:Matrix Metalloproteinase 9; D000069585:Filgrastim