Genetic Influences Determining Progenitor Cell Mobilization and Leukocytosis Induced by Granulocyte Colony-Stimulating Factor

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2736-2744 ◽  
Author(s):  
Andrew W. Roberts ◽  
Simon Foote ◽  
Warren S. Alexander ◽  
Clare Scott ◽  
Lorraine Robb ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Progenitor Cell ◽  
Inbred Strains ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Gm Csf ◽  
Cell Mobilization ◽  
Stimulating Factor

Abstract The mechanisms involved in the mobilization of progenitor cells into the blood by granulocyte colony-stimulating factor (G-CSF ) and other cytokines are poorly understood. To identify important influences on this complex process, in vivo murine models were used. Granulocyte-macrophage colony-stimulating factor (GM-CSF ) transgenic, Max41 transgenic, W/WV, Mpl-null, GM-CSF receptor (β chain)-null mice, wild-type littermate controls, and six inbred strains of mice were injected with 200 μg/kg/d G-CSF for 5 days. Three parameters of response were monitored: white blood cell count (WCC), peripheral blood progenitor cell (PBPC) numbers, and spleen weight. In all genotypes studied, G-CSF induced increases in these three parameters. However, PBPC mobilization in W/WV and Mpl-null mice was only 30% and 9%, respectively, of that observed in wild-type mice. In contrast, perturbations of GM-CSF signalling had no demonstrable effect on in vivo responses to G-CSF. Broad variability was evident between inbred strains for each parameter of the response to G-CSF. A 10-fold range in response was observed for circulating progenitor cell numbers, similar to that observed for normal human subjects receiving G-CSF. The interstrain differences were in the distribution of mature and progenitor cells between peripheral blood, bone marrow, and spleen rather than in the total numbers of these cells in the body. Results of an F2 intercross of low-responding C57BL/6 and intermediate-responding SJL mice indicated that regulation of progenitor cell mobilization is a complex genetic trait, that there is a correlation between this trait and WCC response (r2 = .5), and that this approach may serve as a useful model for the identification of genes involved in the mobilization process.

scholarly journals Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo

Blood ◽  
1990 ◽  
Vol 75 (10) ◽  
pp. 1951-1959 ◽  
Author(s):  
AR Migliaccio ◽  
G Migliaccio ◽  
DC Dale ◽  
WP Hammond
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cyclic Neutropenia ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Stimulating Factor

Abstract The number and growth factor requirements of committed progenitor cells (colony-forming units-granulocyte/macrophage and burst-forming units- erythroid) in three patients with cyclic neutropenia (two congenital, one acquired) were studied before and during therapy with recombinant human granulocyte colony-stimulating factor (G-CSF; 3 to 10 micrograms/kg/d). When the patients with congenital disease were treated with G-CSF, the cycling of blood cells persisted, but the cycle length was shortened from 21 days to 14 days, and the amplitude of variations in blood counts increased. There was a parallel shortening of the cycle and increase of the amplitude of variations (from two- to three-fold to 10- to 100-fold) in the number of both types of circulating progenitor cells in these two patients. In the patient with acquired cyclic neutropenia, cycling of both blood cells and progenitors could not be seen. In cultures deprived of fetal bovine serum, erythroid and myeloid bone marrow progenitor cells from untreated patients and from normals differed in growth factor responsiveness. As examples, maximal growth of granulocyte/macrophage (GM) colonies was induced by granulocyte/macrophage (GM)-CSF plus G-CSF in the patients, whereas a combination of GM-CSF, G-CSF and interleukin- 3 (IL-3) was required in the normals, and erythropoietin alone induced fourfold more erythroid bursts from cyclic neutropenic patients than from normal donors (46% versus 11% of the maximal colony number, respectively). The growth factor responsiveness of marrow progenitor cells slightly changed during the treatment toward the values observed with normal progenitors. These results indicate that treatment with G- CSF not only ameliorated the neutropenia, but also increased the amplitude and the frequency of oscillation of circulating progenitor cell numbers. These data are consistent with the hypothesis that G-CSF therapy affects the proliferation of the hematopoietic stem cell.

Chemotherapy with Granulocyte Colony Stimulating Factor (G-CSF) Alone Versus Granulocyte Colony Stimulating Factor (G-CSF) Plus Granulocyte-Macrophage Stimulating Factor (GM-CSF) for Hematopoietic Progenitor Cell Mobilization in Patients with Relapsed Non-Hodgkin’s Lymphomas (NHLs).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1900-1900
Author(s):  
Chitra Hosing ◽  
Mark Munsell ◽  
Uday Popat ◽  
Martin Körbling ◽  
Rosamar Valverde ◽  
...  
Keyword(s):  
Success Rate ◽  
Clinical Outcomes ◽  
Progenitor Cell ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Cell Mobilization ◽  
Stimulating Factor ◽  
Graft Composition

Abstract Both G-CSF and GM-CSF (alone or in combination) may be used for mobilization of hematopoietic progenitor cells in patients undergoing autologous stem cell transplantation (ASCT). It has been suggested that GM-CSF use during mobilization may impact graft composition and therefore clinical outcomes. METHODS: We prospectively evaluated patients ≤ 70 years old with relapsed CD20+ NHL who were candidates for ASCT. Additional eligibility criteria included adequate marrow and organ function. Patients with history of pelvic radiation, > 3 prior chemoregimens or > 6 cycles of fludarabine chemotherapy were excluded. Patients recieved chemotherapy with ifosfamide 3.33 g/m2 daily × 3 days, etoposide 150 mg/m2 × 6 doses and rituximab (375 mg/m2 on day 1 and 1 g/m2 on day 8). Using a Bayesian adaptive randomization based on treatment outcomes, patient’s were randomized to receive G-CSF 12 μg/kg/d (Group G) or G-CSF 12 μg/kg/d plus GM-CSF 500 μg/d (Group G/GM). We assumed that the success rate for each treatment arm had a β prior distribution with mean 0.90 and variance 0.03. Cytokines started 24 hours after completion of chemotherapy and continued until completion of apheresis. RESULTS: Forty-three patients were randomized to Group G and 41 patients to Group G/GM. In each arm 1 patient withdrew consent after randomization. Baseline characteristics were similar in the 2 groups (Table 1). Both regimens were equally well tolerated. Data are presented as intent to treat analysis. Thirty-nine patients (90.7%) in Group G and 35 patients (85.4%) in Group G/GM collected ≥ 4 × 106 CD34+ cells/kg. The probability that Group G has a higher success rate than Group G/GM is 0.778. The median CD34+ cell dose collected was 10.3 × 106/kg (range, 0.1–59) and 7.5 × 106/kg (range, 0.7–73) in Groups G and G/GM respectively (P=NS). A median of 2 apheresis procedures were required in both arms. Seventy-three patients have undergone ASCT. After a median follow up time of 14.5 months (range, 0.6–38.5) in Group G and 14.0 months (range, 1.1–39.9) in Group G/GM, the 3 year PFS is 75% (95% CI 57.9–99.4) and 77% (95% CI 65–91.5) respectively (P=0.41). CONCLUSION: Our study does not support the hypothesis that using G-CSF plus GM-CSF versus G-CSF alone for progenitor cell mobilization alters graft composition in a way that impacts clinical outcomes after ASCT for NHLs. Baseline Patient Characteristics *Missing data 1 patient G-CSF, N (%) G-CSF + GM-CSF, N (%) 43 (51) 41 (49) AGE <39 4 (9.3) 3 (7.3) 40–59 29 (57.4) 26 (63.5) >59 10 (23.2) 12 (29.3) GENDER (Male/Female) 29/14 (67.4/32.6) 24/17 (58.5/41.5) HISTOLOGY Low grade 4 (9.3) 7 (17.1) Intermediate grade 39 (90.7) 34 (82.9) ANN ARBOR STAGE >I 18 (41.9) 18 (43.9) LDH>Normal* 15 (34.9) 11 (27.5) Figure Figure

scholarly journals Hematopoietic progenitors in cyclic neutropenia: effect of granulocyte colony-stimulating factor in vivo

Blood ◽  
1990 ◽  
Vol 75 (10) ◽  
pp. 1951-1959 ◽  
Author(s):  
AR Migliaccio ◽  
G Migliaccio ◽  
DC Dale ◽  
WP Hammond
Keyword(s):  
Growth Factor ◽  
Progenitor Cells ◽  
Blood Cells ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Cyclic Neutropenia ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Stimulating Factor

The number and growth factor requirements of committed progenitor cells (colony-forming units-granulocyte/macrophage and burst-forming units- erythroid) in three patients with cyclic neutropenia (two congenital, one acquired) were studied before and during therapy with recombinant human granulocyte colony-stimulating factor (G-CSF; 3 to 10 micrograms/kg/d). When the patients with congenital disease were treated with G-CSF, the cycling of blood cells persisted, but the cycle length was shortened from 21 days to 14 days, and the amplitude of variations in blood counts increased. There was a parallel shortening of the cycle and increase of the amplitude of variations (from two- to three-fold to 10- to 100-fold) in the number of both types of circulating progenitor cells in these two patients. In the patient with acquired cyclic neutropenia, cycling of both blood cells and progenitors could not be seen. In cultures deprived of fetal bovine serum, erythroid and myeloid bone marrow progenitor cells from untreated patients and from normals differed in growth factor responsiveness. As examples, maximal growth of granulocyte/macrophage (GM) colonies was induced by granulocyte/macrophage (GM)-CSF plus G-CSF in the patients, whereas a combination of GM-CSF, G-CSF and interleukin- 3 (IL-3) was required in the normals, and erythropoietin alone induced fourfold more erythroid bursts from cyclic neutropenic patients than from normal donors (46% versus 11% of the maximal colony number, respectively). The growth factor responsiveness of marrow progenitor cells slightly changed during the treatment toward the values observed with normal progenitors. These results indicate that treatment with G- CSF not only ameliorated the neutropenia, but also increased the amplitude and the frequency of oscillation of circulating progenitor cell numbers. These data are consistent with the hypothesis that G-CSF therapy affects the proliferation of the hematopoietic stem cell.

scholarly journals In vitro and in vivo hematopoietic effect of mutant human granulocyte colony-stimulating factor [see comments]

Blood ◽  
1990 ◽  
Vol 75 (9) ◽  
pp. 1788-1793 ◽  
Author(s):  
M Okabe ◽  
M Asano ◽  
T Kuga ◽  
Y Komatsu ◽  
M Yamasaki ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Intravenous Injection ◽  
Specific Activity ◽  
High Specific Activity ◽  
Daily Injection ◽  
Total Leukocyte Count ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor

About 100 derivatives of human recombinant granulocyte colony- stimulating factor (rhG-CSF) were created by various gene-mutagenic techniques, and KW-2228, in which amino acids were replaced at five positions of N-terminal region of intact rhG-CSF, was picked up and evaluated for its biologic and physicochemical properties in comparison with intact rhG-CSF. KW-2228 showed two to four times higher specific activity than that of intact rhG-CSF in mouse and/or human bone marrow progenitor cells by colony-forming unit assay in soft agar, and by cell- proliferation assay in liquid culture. KW-2228 showed a potency to increase peripheral neutrophil counts when it was administered to normal C3H/He mice by single intravenous injection. Increase of total leukocyte count and neutrophils was observed, with peak level at 8 to 12 hours at low doses (0.5 to 1.0 micrograms/mouse), and the highest level was maintained for 24 to 30 hours at high doses (5 to 10 micrograms/mouse). The granulopoietic effect of KW-2228 was examined by several doses of single course (once daily for 10 days) or multiple courses (twice daily injection for 5 days followed by cessation for 9 days on one cycle, 3 cycles in total) of treatment. KW-2228 showed higher activity than that of rhG-CSF, especially at sub-optimal doses of multiple courses of treatment. Furthermore, KW-2228 was found to be more stable physicochemically and biologically than intact rhG-CSF, especially under thermal conditions at 56 degrees C and in the human plasma at 37 degrees C, suggesting a protease resistancy. Pharmacokinetic study showed that plasma concentration of KW-2228 assayed for its bioactivity maintained a higher level than that of intact rhG-CSF for 60 minutes after intravenous injection of this protein to normal mice. Those results suggest that KW-2228 might show a superior in vivo hematopoietic effect to intact rhG-CSF due to its high specific activity to progenitor cells, and also due to its improved physicochemical, biologic, and pharmacokinetic stability in host animals.

scholarly journals Stem cell factor in combination with granulocyte colony-stimulating factor (CSF) or granulocyte-macrophage CSF synergistically increases granulopoiesis in vivo

Blood ◽  
1991 ◽  
Vol 78 (8) ◽  
pp. 1954-1962 ◽  
Author(s):  
TR Ulich ◽  
J del Castillo ◽  
IK McNiece ◽  
ES Yi ◽  
CP Alzona ◽  
...  
Keyword(s):  
Stem Cell ◽  
Peripheral Blood ◽  
Stem Cell Factor ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Colony Forming Unit ◽  
Stimulating Factor ◽  
Synergistic Increase

Abstract Recombinant rat stem cell factor (rrSCF) and recombinant human granulocyte colony-stimulating factor (G-CSF) coinjected for 1 week in rats cause a synergistic increase in mature marrow neutrophils accompanied by a striking decrease in erythroid and lymphoid marrow elements. The spleens of the same rats show increased granulopoiesis as well as increased erythropoiesis as compared with the spleens of rats treated with either growth factor alone. Splenic extramedullary erythropoiesis may act to compensate for the decrease in marrow erythropoiesis. The coinjection of rrSCF and G-CSF causes an increase in marrow mast cells at the end of 1 week, but the increase is much less than in rrSCF-alone-treated rats. The combination of rrSCF and G- CSF increases the rate of release of marrow neutrophils into the circulation and causes a dramatic synergistic peripheral neutrophilia, beginning especially after 4 days of treatment. Colony-forming assays of all experimental groups showed a synergistic increase in colony- forming unit granulocyte-macrophage (CFU-GM) in the marrow, but not in peripheral blood, after coincubation with SCF plus granulocyte- macrophage CSF (GM-CSF) as opposed to GM-CSF alone, showing anatomic compartmentalization between a more primitive marrow CFU-GM subset and a more mature peripheral blood CFU-GM subset. In vivo daily administration of SCF plus GM-CSF results in a synergistic increase in marrow neutrophils, but not the striking synergistic increase in circulating neutrophils that is observed with SCF plus G-CSF.

scholarly journals Recombinant rat stem cell factor synergizes with recombinant human granulocyte colony-stimulating factor in vivo in mice to mobilize peripheral blood progenitor cells that have enhanced repopulating potential

Blood ◽  
1993 ◽  
Vol 82 (6) ◽  
pp. 1720-1723 ◽  
Author(s):  
RA Briddell ◽  
CA Hartley ◽  
KA Smith ◽  
IK McNiece
Keyword(s):  
Stem Cell ◽  
Progenitor Cells ◽  
Peripheral Blood ◽  
Stem Cell Factor ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Blood Progenitor Cells ◽  
Stimulating Factor ◽  
Synergistic Increase

Abstract Splenectomized mice treated for 7 days with pegylated recombinant rat stem cell factor (rrSCF-PEG) showed a dose-dependent increase in peripheral blood progenitor cells (PBPC) that have enhanced in vivo repopulating potential. A dose of rrSCF-PEG at 25 micrograms/kg/d for 7 days produced no significant increase in PBPC. However, when this dose of rrSCF-PEG was combined with an optimal dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF; 200 micrograms/kg/d), a synergistic increase in PBPC was observed. Compared with treatment with rhG-CSF alone, the combination of rrSCF-PEG plus rhG-CSF resulted in a synergistic increase in peripheral white blood cells, in the incidence and absolute numbers of PBPC, and in the incidence and absolute numbers of circulating cells with in vivo repopulating potential. These data suggest that low doses of SCF, which would have minimal, if any, effects in vivo, can synergize with optimal doses of rhG-CSF to enhance the mobilization of PBPC stimulated by rhG-CSF alone.

Randomized Cross-Over Trial of Progenitor-Cell Mobilization: High-Dose Cyclophosphamide Plus Granulocyte Colony-Stimulating Factor (G-CSF) Versus Granulocyte-Macrophage Colony-Stimulating Factor Plus G-CSF

2000 ◽  
Vol 18 (9) ◽  
pp. 1824-1830 ◽  
Author(s):  
Omer N. Koç ◽  
Stanton L. Gerson ◽  
Brenda W. Cooper ◽  
Mary Laughlin ◽  
Howard Meyerson ◽  
...  
Keyword(s):  
Progenitor Cell ◽  
Hematopoietic Progenitor Cell ◽  
High Dose ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Hematopoietic Progenitor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

PURPOSE: Patient response to hematopoietic progenitor-cell mobilizing regimens seems to vary considerably, making comparison between regimens difficult. To eliminate this inter-patient variability, we designed a cross-over trial and prospectively compared the number of progenitors mobilized into blood after granulocyte-macrophage colony-stimulating factor (GM-CSF) days 1 to 12 plus granulocyte colony-stimulating factor (G-CSF) days 7 to 12 (regimen G) with the number of progenitors after cyclophosphamide plus G-CSF days 3 to 14 (regimen C) in the same patient. PATIENTS AND METHODS: Twenty-nine patients were randomized to receive either regimen G or C first (G1 and C1, respectively) and underwent two leukaphereses. After a washout period, patients were then crossed over to the alternate regimen (C2 and G2, respectively) and underwent two additional leukaphereses. The hematopoietic progenitor-cell content of each collection was determined. In addition, toxicity and charges were tracked. RESULTS: Regimen C (n = 50) resulted in mobilization of more CD34+ cells (2.7-fold/kg/apheresis), erythroid burst-forming units (1.8-fold/kg/apheresis), and colony-forming units–granulocyte-macrophage (2.2-fold/kg/apheresis) compared with regimen G given to the same patients (n = 46; paired t test, P < .01 for all comparisons). Compared with regimen G, regimen C resulted in better mobilization, whether it was given first (P = .025) or second (P = .02). The ability to achieve a target collection of ≥ 2 × 106 CD34+ cells/kg using two leukaphereses was 50% after G1 and 90% after C1. Three of the seven patients in whom mobilization was poor after G1 had ≥ 2 × 106 CD34+ cells/kg with two leukaphereses after C2. In contrast, when regimen G was given second (G2), seven out of 10 patients failed to achieve the target CD34+ cell dose despite adequate collections after C1. Thirty percent of the patients (nine of 29) given regimen C were admitted to the hospital because of neutropenic fever for a median duration of 4 days (range, 2 to 10 days). The higher cost of regimen C was balanced by higher CD34+ cell yield, resulting in equivalent charges based on cost per CD34+ cell collected. CONCLUSION: We report the first clinical trial that used a cross-over design showing that high-dose cyclophosphamide plus G-CSF results in mobilization of more progenitors then GM-CSF plus G-CSF when tested in the same patient regardless of sequence of administration, although the regimen is associated with greater morbidity. Patients who fail to achieve adequate mobilization after regimen G can be treated with regimen C as an effective salvage regimen, whereas patients who fail regimen C are unlikely to benefit from subsequent treatment with regimen G. The cross-over design allowed detection of significant differences between regimens in a small cohort of patients and should be considered in design of future comparisons of mobilization regimens.

Erythropoietin receptor haploinsufficiency and in vivo interplay with granulocyte-macrophage colony-stimulating factor and interleukin 3

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2603-2605 ◽  
Author(s):  
Armin G. Jegalian ◽  
Adriana Acurio ◽  
Glenn Dranoff ◽  
Hong Wu
Keyword(s):  
Erythropoietin Receptor ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Definitive Erythropoiesis ◽  
Stimulating Factor

Erythropoietin (EPO) and its receptor (EPOR) are critical for definitive erythropoiesis, as mice lacking either gene product die during embryogenesis with severe anemia. Here we demonstrate that mice expressing just one functional allele of the EpoR have lower hematocrits and die more frequently than do wild-type littermates on anemia induction. Furthermore, EpoR+/−erythroid colony-forming unit (CFU-E) progenitors are reduced both in frequency and in responsiveness to EPO stimulation. To evaluate the interaction between EPO and granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin 3 (IL-3),GM-CSF−/− orIL-3−/− mice were interbred withEpoR+/− mice. Deletion of either GM-CSF or IL-3 also leads to reduction in CFU-E numbers and hematocrits but does not significantly alter steady-state erythroid burst-forming unit numbers. These results suggest EpoR haploinsufficiency and promotion of in vivo erythropoiesis by GM-CSF and IL-3.

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