scholarly journals Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Prevents Dissemination and Induces Remission of Juvenile Myelomonocytic Leukemia in Engrafted Immunodeficient Mice

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4910-4917 ◽  
Author(s):  
Per O. Iversen ◽  
Ian D. Lewis ◽  
Suzanne Turczynowicz ◽  
Henrik Hasle ◽  
Charlotte Niemeyer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Myelomonocytic Leukemia ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Myelomonocytic Leukemia ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor α (TNFα) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFα monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.

scholarly journals Inhibition of Granulocyte-Macrophage Colony-Stimulating Factor Prevents Dissemination and Induces Remission of Juvenile Myelomonocytic Leukemia in Engrafted Immunodeficient Mice

Blood ◽  
1997 ◽  
Vol 90 (12) ◽  
pp. 4910-4917 ◽  
Author(s):  
Per O. Iversen ◽  
Ian D. Lewis ◽  
Suzanne Turczynowicz ◽  
Henrik Hasle ◽  
Charlotte Niemeyer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Juvenile Myelomonocytic Leukemia ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Myelomonocytic Leukemia ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF ) and tumor necrosis factor α (TNFα) have been implicated in the pathogenesis of the fatal childhood disease termed juvenile myelomonocytic leukemia (JMML). We used a severe combined immunodeficient/nonobese diabetic (SCID/NOD) mouse model of JMML and examined the effect of inhibiting these cytokines in vivo with the human GM-CSF antagonist and apoptotic agent E21R and the anti-TNFα monoclonal antibody (MoAb) cA2 on JMML cell growth and dissemination in vivo. We show here that JMML cells repopulated to high levels in the absence of exogeneous growth factors. Administration of E21R at the time of transplantation or 4 weeks after profoundly reduced JMML cell load in the mouse bone marrow. In contrast, MoAb cA2 had no effect on its own, but synergized with E21R in virtually eliminating JMML cells from the mouse bone marrow. In the spleen and peripheral blood, E21R eliminated JMML cells, while MoAb cA2 had no effect. Importantly, studies of mice engrafted simultaneously with cells from both normal donors and from JMML patients showed that E21R preferentially eliminated leukemic cells. This is the first time a specific GM-CSF inhibitor has been used in vivo, and the results suggest that GM-CSF plays a major role in the pathogenesis of JMML. E21R might offer a novel and specific approach for the treatment of this aggressive leukemia in man.

scholarly journals M-CSF and GM-CSF Regulation of STAT5 Activation and DNA Binding in Myeloid Cell Differentiation is Disrupted in Nonobese Diabetic Mice

2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
B. Rumore-Maton ◽  
J. Elf ◽  
N. Belkin ◽  
B. Stutevoss ◽  
F. Seydel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Differentiation ◽  
Myeloid Cell ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Nonobese Diabetic ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Defects in macrophage colony-stimulating factor (M-CSF) signaling disrupt myeloid cell differentiation in nonobese diabetic (NOD) mice, blocking myeloid maturation into tolerogenic antigen-presenting cells (APCs). In the absence of M-CSF signaling, NOD myeloid cells have abnormally high granulocyte macrophage colony-stimulating factor (GM-CSF) expression, and as a result, persistent activation of signal transducer/activator of transcription 5 (STAT5). Persistent STAT5 phosphorylation found in NOD macrophages is not affected by inhibiting GM-CSF. However, STAT5 phosphorylation in NOD bone marrow cells is diminished if GM-CSF signaling is blocked. Moreover, if M-CSF signaling is inhibited, GM-CSF stimulationin vitrocan promote STAT5 phosphorylation in nonautoimmune C57BL/6 mouse bone marrow cultures to levels seen in the NOD. These findings suggest that excessive GM-CSF production in the NOD bone marrow may interfere with the temporal sequence of GM-CSF and M-CSF signaling needed to mediate normal STAT5 function in myeloid cell differentiation gene regulation.

scholarly journals Effect of mouse interferon on growth and differentiation of mouse bone marrow cells stimulated by two different types of colony-stimulating factor

Blood ◽  
1983 ◽  
Vol 62 (3) ◽  
pp. 597-601 ◽  
Author(s):  
Y Yamamoto-Yamaguchi ◽  
M Tomida ◽  
M Hozumi
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Mouse Bone Marrow Cells ◽  
Marrow Cells

Abstract The effects of mouse L-cell interferon (IFN) on growth of mouse bone marrow cells and their differentiation into macrophages and granulocytes were investigated in a liquid suspension culture system with two different types of colony-stimulating factor (CSF). Within 7 days, most bone marrow cells differentiated into macrophages in the presence of macrophage colony-stimulating factor (M-CSF) derived from mouse fibroblast L929 cells, but into both granulocytes (40%) and macrophages (23%) in the presence of a granulocyte-macrophage colony- stimulating factor (GM-CSF) from mouse lung tissue. IFN inhibited growth of bone marrow cells with both M-CSF and GM-CSF, but had 20 times more effect on bone marrow cells stimulated with M-CSF than on those stimulated with GM-CSF. A low concentration of IFN (50 IU/ml) stimulated production of macrophages by GM-CSF in liquid culture medium, whereas it selectively inhibited colony formation of macrophages in semisolid agar culture. IFN caused no detectable block of late stages of differentiation; mature macrophages and granulocytes were produced even when cell proliferation was inhibited by IFN. These results indicate that IFN preferentially affects growth and differentiation of the cell lineage of macrophages among mouse bone marrow cells.

scholarly journals Effect of mouse interferon on growth and differentiation of mouse bone marrow cells stimulated by two different types of colony-stimulating factor

Blood ◽  
1983 ◽  
Vol 62 (3) ◽  
pp. 597-601 ◽  
Author(s):  
Y Yamamoto-Yamaguchi ◽  
M Tomida ◽  
M Hozumi
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Mouse Bone Marrow ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Mouse Bone Marrow Cells ◽  
Marrow Cells

The effects of mouse L-cell interferon (IFN) on growth of mouse bone marrow cells and their differentiation into macrophages and granulocytes were investigated in a liquid suspension culture system with two different types of colony-stimulating factor (CSF). Within 7 days, most bone marrow cells differentiated into macrophages in the presence of macrophage colony-stimulating factor (M-CSF) derived from mouse fibroblast L929 cells, but into both granulocytes (40%) and macrophages (23%) in the presence of a granulocyte-macrophage colony- stimulating factor (GM-CSF) from mouse lung tissue. IFN inhibited growth of bone marrow cells with both M-CSF and GM-CSF, but had 20 times more effect on bone marrow cells stimulated with M-CSF than on those stimulated with GM-CSF. A low concentration of IFN (50 IU/ml) stimulated production of macrophages by GM-CSF in liquid culture medium, whereas it selectively inhibited colony formation of macrophages in semisolid agar culture. IFN caused no detectable block of late stages of differentiation; mature macrophages and granulocytes were produced even when cell proliferation was inhibited by IFN. These results indicate that IFN preferentially affects growth and differentiation of the cell lineage of macrophages among mouse bone marrow cells.

scholarly journals Granulocyte-macrophage colony-stimulating factor-induced antibody- dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3474-3479 ◽  
Author(s):  
BS Charak ◽  
R Agah ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Cellular Cytotoxicity ◽  
Colony Stimulating Factor ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to induce antitumor activity in peripheral blood monocytes. We examined the role of GM-CSF on bone marrow (BM) macrophages in inducing antibody-dependent cellular cytotoxicity (ADCC) against murine and human tumor cells in vitro and in vivo with the aim of applying this approach in an autologous bone marrow transplantation (BMT) setting. GM- CSF induced a potent ADCC in BM macrophages against a murine melanoma in vitro. Treatment with GM-CSF alone or with antibody alone had no effect, whereas therapy with combination of both these agents resulted in a significant reduction in dissemination of melanoma both in a nontransplant as well as in BMT settings, with results being more optimal in the latter setting. Adoptive transfer of BM macrophages harvested from mice undergoing therapy with GM-CSF plus antibody significantly reduced the dissemination of melanoma in secondary recipients but only after irradiation, not in intact mice. GM-CSF also induced significant ADCC in human BM macrophages against a melanoma and a lymphoma in vitro and against a lymphoma implanted in nude mice in vivo. Again, these effects were more optimal after chemotherapy. These data suggest that treatment with GM-CSF plus tumor-specific monoclonal antibodies after BMT may induce an antitumor effect and help eradicate the minimal residual disease.

scholarly journals Differential effects of sequential, simultaneous, and single agent interleukin-3 and granulocyte-macrophage colony-stimulating factor on megakaryocyte maturation and platelet response in primates

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2479-2485 ◽  
Author(s):  
CP Stahl ◽  
EF Winton ◽  
MC Monroe ◽  
E Haff ◽  
RC Holman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Agent ◽  
Colony Stimulating Factor ◽  
Platelet Response ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) following interleukin-3 (IL-3) priming has been shown to increase thrombopoiesis. To elucidate the comparative abilities of IL-3 and GM- CSF in influencing megakaryocyte development in vivo, serial bone marrow analyses were performed on rhesus monkeys treated with 5 micrograms/kg/d of IL-3 and 5 micrograms/kg/d of GM-CSF sequentially for 4 days each, simultaneously for 8 days, and as single agents for 8 days. Platelet counts maximally increased to a mean of 7.5 x 10(5)/microL (n = 3) on days 11 through 12 in monkeys treated with sequential IL-3/GM-CSF. In contrast, neither IL-3 alone nor simultaneously administered IL-3/GM-CSF elicited increases in thrombopoiesis between days 3 and 15. GM-CSF elicited a variable platelet response. Megakaryocyte ploidy distributions were significantly (P < .001) shifted between days 7 and 10 in monkeys treated sequentially and between days 3 and 15 in monkeys treated with combined IL-3/GM-CSF and with GM-CSF alone but not in monkeys treated with IL-3 alone. The changes in mean DNA content and megakaryocyte size, as determined by digital image analysis, were larger in monkeys treated with sequential IL-3/GM-CSF and with GM-CSF alone than in simultaneously treated monkeys. In addition, sequentially but not simultaneously treated monkeys showed increased numbers of megakaryocytes on bone marrow biopsy. We conclude that administration of IL-3 followed by GM-CSF treatment increases thrombopoiesis by sequentially increasing megakaryocyte numbers and maturation and that these effects are diminished by simultaneous administration of the two cytokines.

scholarly journals Granulocyte-macrophage colony-stimulating factor-induced antibody- dependent cellular cytotoxicity in bone marrow macrophages: application in bone marrow transplantation

Blood ◽  
1993 ◽  
Vol 81 (12) ◽  
pp. 3474-3479 ◽  
Author(s):  
BS Charak ◽  
R Agah ◽  
A Mazumder
Keyword(s):  
Bone Marrow ◽  
Cellular Cytotoxicity ◽  
Colony Stimulating Factor ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been reported to induce antitumor activity in peripheral blood monocytes. We examined the role of GM-CSF on bone marrow (BM) macrophages in inducing antibody-dependent cellular cytotoxicity (ADCC) against murine and human tumor cells in vitro and in vivo with the aim of applying this approach in an autologous bone marrow transplantation (BMT) setting. GM- CSF induced a potent ADCC in BM macrophages against a murine melanoma in vitro. Treatment with GM-CSF alone or with antibody alone had no effect, whereas therapy with combination of both these agents resulted in a significant reduction in dissemination of melanoma both in a nontransplant as well as in BMT settings, with results being more optimal in the latter setting. Adoptive transfer of BM macrophages harvested from mice undergoing therapy with GM-CSF plus antibody significantly reduced the dissemination of melanoma in secondary recipients but only after irradiation, not in intact mice. GM-CSF also induced significant ADCC in human BM macrophages against a melanoma and a lymphoma in vitro and against a lymphoma implanted in nude mice in vivo. Again, these effects were more optimal after chemotherapy. These data suggest that treatment with GM-CSF plus tumor-specific monoclonal antibodies after BMT may induce an antitumor effect and help eradicate the minimal residual disease.

scholarly journals Essential Roles for Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and G-CSF in the Sustained Hematopoietic Response ofListeria monocytogenes–Infected Mice

Blood ◽  
1998 ◽  
Vol 91 (3) ◽  
pp. 863-869 ◽  
Author(s):  
Yifan Zhan ◽  
Graham J. Lieschke ◽  
Dianne Grail ◽  
Ashley R. Dunn ◽  
Christina Cheers
Keyword(s):  
Bone Marrow ◽  
Peritoneal Cavity ◽  
Colony Stimulating Factor ◽  
Wild Type ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Oflisteria Monocytogenes ◽  
Stimulating Factor

The in vivo roles of granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte (G)-CSF were studied in factor-deficient gene-targeted knockout mice infected with the facultative intracellular bacterium Listeria monocytogenes.Previous results showed that G-CSF−/− mice had an underlying selective deficiency in granulopoiesis, but GM-CSF−/− mice had little disturbance in resting hematopoiesis. Nevertheless, in this study it is revealed that 3 days after intraperitoneal infection with 2 × 105Listeria, GM-CSF−/− mice harbored 50-fold more organisms in their spleen and liver than similarly infected wild-type mice. This was accompanied by a severe depletion of bone marrow hematopoietic cells and a deficient inflammatory response in their peritoneal cavity. Thus, GM-CSF is essential for emergency, but not resting, hematopoiesis. In contrast, G-CSF−/− mice were markedly susceptible to low doses (2 × 104) ofListeria intraperitoneally. After infection, the acute (1 day) granulocyte infiltration to the peritoneal cavity was normal compared with wild type, but the more prolonged monocyte response was deficient, reflecting a continued decrease in bone marrow cellularity and hematopoiesis over 3 days, which was not observed in infected wild-type mice. It is thus apparent that G-CSF deficiency affects monocytopoiesis as well as granulopoiesis during infection.

scholarly journals Differential effects of sequential, simultaneous, and single agent interleukin-3 and granulocyte-macrophage colony-stimulating factor on megakaryocyte maturation and platelet response in primates

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2479-2485
Author(s):  
CP Stahl ◽  
EF Winton ◽  
MC Monroe ◽  
E Haff ◽  
RC Holman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Single Agent ◽  
Colony Stimulating Factor ◽  
Platelet Response ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) following interleukin-3 (IL-3) priming has been shown to increase thrombopoiesis. To elucidate the comparative abilities of IL-3 and GM- CSF in influencing megakaryocyte development in vivo, serial bone marrow analyses were performed on rhesus monkeys treated with 5 micrograms/kg/d of IL-3 and 5 micrograms/kg/d of GM-CSF sequentially for 4 days each, simultaneously for 8 days, and as single agents for 8 days. Platelet counts maximally increased to a mean of 7.5 x 10(5)/microL (n = 3) on days 11 through 12 in monkeys treated with sequential IL-3/GM-CSF. In contrast, neither IL-3 alone nor simultaneously administered IL-3/GM-CSF elicited increases in thrombopoiesis between days 3 and 15. GM-CSF elicited a variable platelet response. Megakaryocyte ploidy distributions were significantly (P < .001) shifted between days 7 and 10 in monkeys treated sequentially and between days 3 and 15 in monkeys treated with combined IL-3/GM-CSF and with GM-CSF alone but not in monkeys treated with IL-3 alone. The changes in mean DNA content and megakaryocyte size, as determined by digital image analysis, were larger in monkeys treated with sequential IL-3/GM-CSF and with GM-CSF alone than in simultaneously treated monkeys. In addition, sequentially but not simultaneously treated monkeys showed increased numbers of megakaryocytes on bone marrow biopsy. We conclude that administration of IL-3 followed by GM-CSF treatment increases thrombopoiesis by sequentially increasing megakaryocyte numbers and maturation and that these effects are diminished by simultaneous administration of the two cytokines.

scholarly journals A murine cytokine fusion toxin specifically targeting the murine granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor on normal committed bone marrow progenitor cells and GM-CSF-dependent tumor cells

Blood ◽  
1995 ◽  
Vol 86 (7) ◽  
pp. 2732-2740 ◽  
Author(s):  
CH Chan ◽  
BR Blazar ◽  
CR Eide ◽  
RJ Kreitman ◽  
DA Vallera
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Leukemia Cells ◽  
Colony Stimulating Factor ◽  
Fusion Toxin ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

A fusion protein was synthesized consisting of the murine granulocyte-macrophage colony-stimulating factor (mGM-CSF) gene spliced to a truncated form of the diphtheria toxin (DT390) gene coding for a molecule that retained full enzymatic activity, but excluded the native binding domain. The DT390-mGM-CSF hybrid gene was cloned into a vector under the control of an inducible promoter and the protein expressed in Escherichia coli. After induction, a protein was purified from inclusion bodies in accord with the deduced molecular weight of DT390 mGM-CSF. Cell-free studies of the adenosine diphosphate-ribosylating activity of DT390 mGM-CSF showed results that were similar to those of native DT. The DT390 mGM-CSF immunotoxin inhibited FDCP2.1d, a murine myelomonocytic tumor line expressing the GM-CSF receptor with an IC50 (concentration inhibiting 50% activity) of 5 x 10(-11) mol/L. The fusion toxin was specifically cytotoxic and directed by the GM-CSF portion of the molecule because addition of a monoclonal antibody directed against GM-CSF inhibited its ability to kill the cell line. Cell lines that do not express GM-CSF receptor were not inhibited by the fusion toxin. DT390 mGM-CSF was also able to specifically inhibit normal committed bone marrow (BM) progenitor cells as measured in clonal colony-forming unit granulocyte-macrophage assays. Together, these findings indicate that DT390 mGM-CSF may be useful as a novel tool for purging BM of contaminating leukemia cells or in vivo for eliminating residual leukemia cells. Also, it can be used to determine whether committed and/or noncommitted BM progenitor cells express the GM-CSF receptor.

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