Administration of rHuGM-CSF activates monocyte reactive oxygen species secretion and adhesion molecule expression in vivo in patients following high-dose chemotherapy.
Microbicidal and cytocidal products of the respiratory burst and integrin adhesion molecule expression have been studied in monocytes from patients who received rHuGM-CSF during regeneration after high-dose chemotherapy. In this study, administration of rHuGM-CSF after high-dose chemotherapy significantly augmented the secretion of inducible products of the monocyte respiratory burst. Monocyte activation persisted for several weeks after the cessation of GM-CSF therapy. Under in vitro conditions that mimicked gram-negative (LPS) and gram-positive (opsonized Staphylococcus aureus) sepsis, the monocyte responded to such stimulation by exhibiting an enhanced release of hydrogen peroxide at both regeneration and several weeks later (P < 0.001). Similarly, GM-CSF administration significantly augmented the phenotypic expression of the beta 2-integrin adhesion molecules and allowed the leucocyte-specific selectin, LAM-1, and the beta 2-integrins to respond normally to inflammatory stimulation by LPS. We further present evidence that GM-CSF therapy restored the otherwise refractory status of monocytes to inflammatory stimulation that existed in those patients given chemotherapy alone. The restoration of monocyte responsiveness by GM-CSF following high-dose chemotherapy could be a potentially valuable and hitherto not described action of rHuGM-CSF on monocyte function. We conclude that administration of GM-CSF may have the potential for restoring as well as augmenting the anti-microbial and anti-tumour function of the monocyte after high-dose chemotherapy.
Williams
M A
MA
Department of Haematology, London Hospital Medical College.
Kelsey
S M
SM
Collins
P W
PW
Gutteridge
C N
CN
Newland
A C
AC
D000328:Adult; D000942:Antigens, Bacterial / Q000494:pharmacology; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules / Q000097:blood*; D003520:Cyclophosphamide / Q000627:therapeutic use*; D004926:Escherichia coli; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D016023:Integrins / Q000032:analysis; D019041:L-Selectin; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects / Q000276:immunology*; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D016897:Respiratory Burst / Q000187:drug effects; D013211:Staphylococcus aureus / Q000276:immunology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D000942:Antigens, Bacterial; D018821:CD18 Antigens; D015815:Cell Adhesion Molecules; D016023:Integrins; D008070:Lipopolysaccharides; D017382:Reactive Oxygen Species; D011994:Recombinant Proteins; D019041:L-Selectin; D009240:N-Formylmethionine Leucyl-Phenylalanine; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D003520:Cyclophosphamide; D013755:Tetradecanoylphorbol Acetate