title: Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo.
abstract: Peripheral blood stem cell (PBSC) transplantation is successful in improving engraftment without increasing acute graft-versus-host disease (GVHD), despite much larger numbers of T cells in unmanipulated PBSCs than in bone marrow grafts. In mouse models and retrospective human studies, granulocyte colony-stimulating factor (G-CSF) therapy has been associated with less acute GVHD. We studied the effect of G-CSF on interferon (IFN)-gamma and IL-4 expression in CD4(+) lymphocytes. CD4(+) cells co-cultivated with G-CSF and stimulated with PHA or CD3 monoclonal antibodies showed significant decreases in IFN-gamma and increases in IL-4 expression (n = 13; P <. 01). G-CSF appeared to have a direct effect on CD4(+) cells independent of monocytes present in the culture because purified CD4(+) cells exposed to G-CSF, washed, and cocultivated with untreated monocytes demonstrated similar changes in IFN-gamma and IL-4 expression, whereas untreated CD4(+) cells cocultured with G-CSF-stimulated monocytes behaved as controls. We then studied peripheral blood mononuclear cells (PBMCs) from G-CSF-mobilized PBSC donors. When their PBMCs were cultured with PHA or CD3 monoclonal antibody, the percent of IFN-gamma-expressing cells decreased by a mean of 55% and 42%, respectively, whereas the percent of IL-4-containing cells increased by a mean of 39% and 58%, respectively, following G-CSF stimulation. Increased apoptosis of IFN-gamma-producing CD4(+) cells was not responsible for the shift in TH1/TH2 subsets. G-CSF-R mRNA was present in both CD4(+) and CD8(+) cells. These results suggest that G-CSF decreases IFN-gamma and increases IL-4 production in vitro and in vivo and likely modulates a balance between TH1 and TH2 cells, an effect that may be important in PBSC transplantation.
authors.affiliation: National Heart, Lung and Blood Institute, National Institutes of Health (NIH), Bethesda, MD, USA.
authors.forename: E M
authors.initials: EM
authors.lastname: Sloand
authors.forename: S
authors.initials: S
authors.lastname: Kim
authors.forename: J P
authors.initials: JP
authors.lastname: Maciejewski
authors.forename: F
authors.initials: F
authors.lastname: Van Rhee
authors.forename: A
authors.initials: A
authors.lastname: Chaudhuri
authors.forename: J
authors.initials: J
authors.lastname: Barrett
authors.forename: N S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis*; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008214:Lymphocytes / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D010835:Phytohemagglutinins / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D016207:Cytokines; D010835:Phytohemagglutinins; D012333:RNA, Messenger; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor; D015847:Interleukin-4; D007371:Interferon-gamma