title: Dexamethasone promotes granulocyte mobilization by prolonging the half-life of granulocyte-colony-stimulating factor in healthy donors for granulocyte transfusions.
abstract: Granulocyte transfusion (GTX) is a potential approach to correcting neutropenia and relieving the increased risk of infection in patients who are refractory to antibiotics. To mobilize enough granulocytes for transfusion, healthy donors are premedicated with granulocyte-colony-stimulating factor (G-CSF) and dexamethasone. Granulocytes have a short circulatory half-life. Consequently, patients need to receive GTX every other day to keep circulating granulocyte counts at an acceptable level. We investigated whether plasma from premedicated donors was capable of prolonging neutrophil survival and, if so, which factor could be held responsible.
  
  
  
  The effects of plasma from G-CSF/dexamethasone-treated donors on neutrophil survival were assessed by annexin-V, CD16. and CXCR4 staining and nuclear morphology. We isolated an albumin-bound protein using α-chymotrypsin and albumin-depletion and further characterized it using protein analysis. The effects of dexamethasone and G-CSF were assessed using mifepristone and G-CSF-neutralizing antibody. G-CSF plasma concentrations were determined by Western blot and Luminex analyses.
  
  
  
  G-CSF/dexamethasone plasma contained a survival-promoting factor for at least 2 days. This factor was recognized as an albumin-associated protein and was identified as G-CSF itself, which was surprising considering its reported half-life of only 4.5 hours. Compared with coadministration of dexamethasone, administration of G-CSF alone to the same GTX donors led to a faster decline in circulating G-CSF levels, whereas dexamethasone itself did not induce any G-CSF, demonstrating a role for dexamethasone in increasing G-CSF half-life.
  
  
  
  Dexamethasone increases granulocyte yield upon coadministration with G-CSF by extending G-CSF half-life. This observation might also be exploited in the coadministration of dexamethasone with other recombinant proteins to modulate their half-life.
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam.
authors.forename: Ida H
authors.initials: IH
authors.lastname: Hiemstra
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam.
authors.forename: John L
authors.initials: JL
authors.lastname: van Hamme
authors.affiliation: Department of Experimental Immunology, Academic Medical Center (AMC).
authors.forename: Machiel H
authors.initials: MH
authors.lastname: Janssen
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam.
authors.forename: Timo K
authors.initials: TK
authors.lastname: van den Berg
authors.affiliation: Department of Blood Cell Research, Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam.|Department of Pediatric Hematology, Immunology, and Infectious Disease, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
mesh_terms: D000328:Adult; D017304:Annexin A5 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D003907:Dexamethasone / Q000008:administration & dosage / Q000493:pharmacokinetics; D000069585:Filgrastim / Q000008:administration & dosage / Q000493:pharmacokinetics; D058851:GPI-Linked Proteins / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D017708:Leukocyte Transfusion; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism*; D010949:Plasma / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D017304:Annexin A5; C527276:CXCR4 protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D019718:Receptors, CXCR4; D017452:Receptors, IgG; D015735:Mifepristone; D003907:Dexamethasone; D000069585:Filgrastim