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)-γ 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-γ 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-γ 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-γ–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-γ–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-γ 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.

Granulocyte–colony‐stimulatory factor: a strong inhibitor of natural killer cell function

“…The significant decrease in production of IFN‐γ does directly correlate with a decrease in the cytotoxic activity. So far, it has only been reported that G‐CSF decreases IFN‐γ secretion in CD4+ cells 35 and TNF‐α secretion in PBMNCs 36 . But the secretion of cytokines like IL‐6 or TNF‐α or the chemokine IL‐8 was also down regulated, although not significant in the in vitro assays.…”

Epigenetic induction of adaptive immune response in multiple myeloma: sequential azacitidine and lenalidomide generate cancer testis antigen‐specific cellular immunity

“…The absence of competing lymphocyte populations could, in this setting, lead to preferential proliferation of oligoclonal T cells in the ALI. Additionally we used GM‐CSF for haematopoietic reconstitution rather than G‐CSF to avoid the T‐helper cell type 2 skewing and T cell hypo‐responsiveness reported with the use of G‐CSF (Sloand et al , ). GM‐CSF also promotes DC differentiation, potentially triggering T cell reactivity against clonal plasma cells over‐expressing CTA in the MRD state.…”

Analysis of the recovery of cryopreserved and thawed CD34+ and CD3+ cells collected for hematopoietic transplantation

“…However, there were two major differences between the related and unrelated donor lymphocyte products studied: 1) all of the unrelated lymphocyte product donors had been given G‐CSF while only about 40% of the related lymphocyte product donors were given G‐CSF and 2) the unrelated donor products had been stored longer before cryopreservation. G‐CSF is known to modulate lymphocyte function and it is possible that G‐CSF–induced changes in CD3+ cells could affect their tolerance of cryopreservation and thawing. It is also possible that prolonged liquid storage of the products before cryopreservation could damage CD3+ cells, thereby reducing their ability to survive the cryopreservation and thawing process.…”