scholarly journals A Specific Stimulator of Granulocyte Colony-Stimulating Factor Accelerates Recovery From Cyclophosphamide-Induced Neutropenia in the Mouse

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 795-802 ◽  
Author(s):  
Jay S. Fine ◽  
Xiao-Yan Cai ◽  
Luminita Justice ◽  
Carl P. Gommoll ◽  
Linda D. Hamilton ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Small Molecular Weight ◽  
Peripheral Blood Mononuclear ◽  
Stimulating Factor

Abstract We have identified a small molecular weight compound, SCH 14988, which specifically stimulates in vitro granulocyte-colony stimulating factor (G-CSF ) production from activated human peripheral blood mononuclear cells and monocytes but not other cytokines or CSFs with hematoregulatory activity. In vivo administration of SCH 14988 to mice rendered neutropenic by cyclophosphamide treatment resulted in the accelerated recovery of the peripheral neutrophil compartment. This activity correlated with increased in vivo G-CSF levels and stimulation of marrow granulopoiesis, and was comparable to that of exogenously administered recombinant human G-CSF. No alterations to other leukocyte populations in peripheral blood, spleen, or the peritoneal cavity were observed. These findings suggest that SCH 14988 may be clinically useful to enhance neutrophil granulopoiesis, as well as to study the mechanisms involved in G-CSF gene regulation.

scholarly journals A Specific Stimulator of Granulocyte Colony-Stimulating Factor Accelerates Recovery From Cyclophosphamide-Induced Neutropenia in the Mouse

Blood ◽  
1997 ◽  
Vol 90 (2) ◽  
pp. 795-802
Author(s):  
Jay S. Fine ◽  
Xiao-Yan Cai ◽  
Luminita Justice ◽  
Carl P. Gommoll ◽  
Linda D. Hamilton ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Small Molecular Weight ◽  
Peripheral Blood Mononuclear ◽  
Stimulating Factor

We have identified a small molecular weight compound, SCH 14988, which specifically stimulates in vitro granulocyte-colony stimulating factor (G-CSF ) production from activated human peripheral blood mononuclear cells and monocytes but not other cytokines or CSFs with hematoregulatory activity. In vivo administration of SCH 14988 to mice rendered neutropenic by cyclophosphamide treatment resulted in the accelerated recovery of the peripheral neutrophil compartment. This activity correlated with increased in vivo G-CSF levels and stimulation of marrow granulopoiesis, and was comparable to that of exogenously administered recombinant human G-CSF. No alterations to other leukocyte populations in peripheral blood, spleen, or the peritoneal cavity were observed. These findings suggest that SCH 14988 may be clinically useful to enhance neutrophil granulopoiesis, as well as to study the mechanisms involved in G-CSF gene regulation.

Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2269-2274 ◽  
Author(s):  
Elaine M. Sloand ◽  
Sonnie Kim ◽  
Jaroslaw P. Maciejewski ◽  
Fritz Van Rhee ◽  
Aniruddho Chaudhuri ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Th2 Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cd4 Cells ◽  
Ifn Γ ◽  
Stimulating Factor

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.

Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2269-2274 ◽  
Author(s):  
Elaine M. Sloand ◽  
Sonnie Kim ◽  
Jaroslaw P. Maciejewski ◽  
Fritz Van Rhee ◽  
Aniruddho Chaudhuri ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Th2 Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cd4 Cells ◽  
Ifn Γ ◽  
Stimulating Factor

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 &lt; .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.

scholarly journals CD14+ cells in granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells induce secretion of interleukin-6 and G-CSF by marrow stroma

Blood ◽  
1996 ◽  
Vol 87 (2) ◽  
pp. 574-580 ◽  
Author(s):  
M Mielcarek ◽  
BA Roecklein ◽  
B Torok-Storb
Keyword(s):  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Stimulating Factor ◽  
Mobilized Peripheral Blood ◽  
Factor G

The ability of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood mononuclear cells (G-PBMCs) to induce secretion of cytokines in primary long-term marrow cultures (LTC) or in the human marrow stromal cell line HS23 was compared with that of marrow mononuclear cells. Equal numbers of G-PBMCs or marrow mononuclear cells were added to stromal cultures, supernatants were harvested at day 4 and levels of interleukin-1 alpha (IL-1 alpha), IL-1 beta, IL-2, IL-6, G-CSF, and tumor necrosis factor alpha (TNF alpha) were determined. G- PBMCs induced 21.4-fold higher levels of IL-6 and 12.5-fold higher levels of G-CSF in LTC cocultures compared with marrow mononuclear cells and induced 20.6-fold more IL-6 and 6.3-fold more G-CSF when added to HS23 cells. Experiments using sorted populations of CD20+, CD3+, and CD14+ cells showed that CD14+ cells within G-PBMCs were responsible for triggering the production of IL-6 and G-CSF. The effect did not require cell-cell contact and was inhibited when neutralizing antibodies to IL-1 alpha and IL-1 beta were used in combination. In these experiments, the greater stimulating ability of G-PBMCs is most likely attributable to the greater number of CD14+ cells in G-PBMCs (26.1+% +/- 2.3%) compared with marrow (2.5% +/- 0.8%), because equal numbers of CD14+ cells sorted from marrow and G-PBMCs showed comparable ability to induce IL-6 and G-CSF when placed directly on stromal cells.

scholarly journals The severe combined immunodeficient-human peripheral blood stem cell (SCID-huPBSC) mouse: a xenotransplant model for huPBSC-initiated hematopoiesis

Blood ◽  
1995 ◽  
Vol 86 (1) ◽  
pp. 89-100 ◽  
Author(s):  
SR Goan ◽  
I Fichtner ◽  
U Just ◽  
L Karawajew ◽  
W Schultze ◽  
...  
Keyword(s):  
Cell Line ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Dose Range ◽  
Human Cells ◽  
Colony Stimulating Factor ◽  
Immunodeficient Mice ◽  
Stimulating Factor

Mononuclear cells (MNCs) containing peripheral blood stem cells (PBSCs) were obtained from solid-tumor patients undergoing mobilizing chemotherapy followed by granulocyte colony-stimulating factor for PBSC transplantation-supported dose-intensified anticancer chemotherapy and were transplanted into unconditioned “nonleaky” young severe combined immunodeficient mice. Multilineage engraftment was shown by flow cytometry and immunocytochemistry using monoclonal antibodies to various human cell surface antigens as well as identification of human immunoglobulin in murine sera. Within a dose range of MNCs suitable for transplantation (10 to 36 x 10(6) cells/graft) the number of CD34+ cells injected (optimal at > 0.7 x 10(6)/graft) determined the yield of human cells produced in recipient animals. Engraftment of hu PBSC preparations resulted in prolonged generation of physiologic levels of human cytokines including interleukin-3 (IL-3), IL-6, and granulocyte- macrophage colony-stimulating factor, which were detectable in the murine blood over a period of at least 4 months. In vivo survival of immature human progenitor cells was preserved even 9 months after transplantation. Because human IL-3 is known to stimulate early hematopoiesis, a rat fibroblast cell line was stably transfected with a retroviral vector carrying the human IL-3 gene and cotransplanted subcutaneously as additional source of growth factor. Cotransplants of this cell line producing sustained in vivo levels of circulating human IL-3 for at least 12 weeks significantly accelerated the process of engraftment of huPBSC and spurred the spread of mature human cells to the murine spleen, liver, thymus, and peripheral blood. Cotransplants of allogeneic human bone marrow stromal cells derived from long-term cultures resulted in a comparable--though less prominent--support of engraftment.

Simvastatin Suppresses Interleukin Iβ Release in Human Peripheral Blood Mononuclear Cells Stimulated With Cholesterol Crystals

2018 ◽  
Vol 23 (6) ◽  
pp. 509-517 ◽  
Author(s):  
Anna J. Boland ◽  
Nisha Gangadharan ◽  
Pierce Kavanagh ◽  
Linda Hemeryck ◽  
Jennifer Kieran ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Peripheral Blood Mononuclear Cells ◽  
Nlrp3 Inflammasome ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Human Peripheral Blood ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Statins are mainstream therapy in the treatment and prevention of cardiovascular disease through inhibitory effects on cholesterol synthesis. However, statins’ beneficial effects in cardiovascular disease may also be attributable to their role as anti-inflammatory mediators. Here, we investigated the effects of simvastatin treatment on expression levels of interleukin (IL) 1β in both patient with hyperlipidemia and healthy human peripheral blood mononuclear cells (PBMCs) using cholesterol crystals (CC), a cardiovascular pathogenic stimulus for activation of the NOD-like receptor pyrin domain–containing protein 3 (NLRP3) inflammasome. Cholesterol crystal-induced NLRP3 inflammasome activation was used to trigger maturation and release of IL-1β in PBMCs. Specifically, isolated PBMCs from patients with hyperlipidemia at baseline and following 8 weeks of in vivo treatment with simvastatin (10-20 mg) daily were stimulated with lipopolysaccharide (LPS; 100 ng/mL) for 3 hours to induce proIL-Iβ expression followed by CC (2 mg/mL) stimulation for further 18 hours to activate the NLRP3 inflammasome complex to induce maturation/activation of IL-1β. Peripheral blood mononuclear cells were also isolated from healthy donors and stimulated in vitro with simvastatin (50, 25, 5, and 2 µmol/L) prior to stimulation with LPS and CC as described above. The effects of simvastatin treatment on levels of IL-1β expression were determined by enzyme-linked immunosorbent assay and western blot. Both in vitro and in vivo treatments with simvastatin led to a significant reduction in the levels of expression of IL-1β in response to stimulation with CC. Simvastatin inhibits the expression and activation of IL-1β induced by CC in PBMCs, which may contribute to its protective role in patients with cardiovascular disease.

scholarly journals Syngeneic transplantation with peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor

Blood ◽  
1993 ◽  
Vol 82 (7) ◽  
pp. 1981-1984 ◽  
Author(s):  
CH Weaver ◽  
CD Buckner ◽  
K Longin ◽  
FR Appelbaum ◽  
S Rowley ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Median Time ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Stimulating Factor

Abstract Five syngeneic transplants were performed in four patients following myeloablative therapy using unmodified peripheral blood mononuclear cells (PBMCs) collected after the administration of recombinant human granulocyte colony stimulating factor (rhG-CSF) to normal donors. The only toxicity experienced by the four normal donors was bone pain. Four patients received two collections of PBMCs, and a second transplant was performed in one patient with one collection. The patients received a median of 20.53 x 10(8) total nucleated cells/kg (range 20 to 25.5), 11.3 x 10(8) total mononuclear cells/kg (range 6.52 to 17.2), 113.1 x 10(4)/kg CFU-GM (range 46.7 to 211.8) and 9.6 x 10(6) CD34+ cells/kg (range 1.6 to 12.6) Post-transplant growth factors were not administered. The median time to an absolute neutrophil count greater than 0.5 x 10(9)/L was 14 days (range 10 to 18). The median time to platelet transfusion independence was 11 days (range 10 to 13). Two patients had the number of CD3+ T lymphocytes determined in the pheresis product. An average of 3.04 x 10(10) CD3+ cells were collected per pheresis. This represents an approximate 1 log increase over the number of T lymphocytes in a typical bone marrow transplant. Rh-GCSF can be used to mobilize peripheral blood progenitor cells from normal donors with minimal toxicity. Studies of allogeneic transplants using PBMCs collected after rhG-CSF administration to determine permanent grafting ability and the incidence and severity of graft-versus-host disease are warranted.

scholarly journals Impaired Induction of the CD28-Responsive Complex in Granulocyte Colony-Stimulating Factor Mobilized CD4 T Cells

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 347-352 ◽  
Author(s):  
Junji Tanaka ◽  
Marco Mielcarek ◽  
Beverly Torok-Storb
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells ◽  
Stimulating Factor

Abstract Use of the CD28/B7 costimulatory signal for T-cell activation was analyzed in granulocyte colony-stimulating factor (G-CSF) mobilized peripheral blood mononuclear cells (G-PBMCs) and in peripheral blood mononuclear cells obtained before administration of G-CSF (preG-PBMCs). CTLA4Ig inhibition of OKT3-stimulated proliferation was significantly lower in G-PBMCs compared with preG-PBMCs (39.9% ± 5.6% and 72.2% ± 5.4%, respectively; P < .001). Furthermore, as shown in electrophoretic mobility-shift assays, the inducible level of the T-cell transcription factor CD28 responsive complex (CD28RC) was suppressed in CD4 cells derived from G-PBMC. However, depletion of CD14 cells from G-PBMCs restored CD28RC induction to normal levels. Taken together, these findings suggest that the large number of CD14 monocytes in G-PBMCs may limit T-cell responsiveness by suppressing the induction of the CD28RC.

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