Journal articles on the topic 'GM-CSF'
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1
Sands, Bruce E. "GM-CSF." Inflammatory Bowel Diseases 12 (April 2006): S12. http://dx.doi.org/10.1097/00054725-200604002-00024.
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Ratto, Alessandra, Claudio Petterino, Tullio Florio, and Federica Barbieri. "Goat anti-human GM-CSF recognizes canine GM-CSF." Veterinary Clinical Pathology 41, no. 1 (March 2012): 3–4. http://dx.doi.org/10.1111/j.1939-165x.2012.00407.x.
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&NA;. "DT388-GM-CSF." Inpharma Weekly &NA;, no. 1152 (August 1998): 7. http://dx.doi.org/10.2165/00128413-199811520-00012.
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Senzer, N., C. Bedell, and J. Nemunaitis. "OncoVEX(GM-CSF)." Drugs of the Future 35, no. 6 (2010): 449. http://dx.doi.org/10.1358/dof.2010.035.06.1500437.
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Senzer, N., C. Bedell, and J. Nemunaitis. "OncoVEX(GM-CSF)." Drugs of the Future 35, no. 6 (2010): 449. http://dx.doi.org/10.1358/dof.2010.35.6.1500437.
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Tazawa, Ryushi, and Koh Nakata. "GM-CSF Therapy for Pulmonary Alveolar Proteinosis." Nihon Naika Gakkai Zasshi 99, no. 7 (2010): 1623–27. http://dx.doi.org/10.2169/naika.99.1623.
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Reed, Jacquelyn A., Machiko Ikegami, Eli R. Cianciolo, Wei Lu, Patricia S. Cho, William Hull, Alan H. Jobe, and Jeffrey A. Whitsett. "Aerosolized GM-CSF ameliorates pulmonary alveolar proteinosis in GM-CSF-deficient mice." American Journal of Physiology-Lung Cellular and Molecular Physiology 276, no. 4 (April 1, 1999): L556—L563. http://dx.doi.org/10.1152/ajplung.1999.276.4.l556.
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Surfactant proteins and phospholipids accumulate in the alveolar spaces and lung tissues of mice deficient in granulocyte-macrophage colony-stimulating factor (GM-CSF), with pathological findings resembling the histology seen in the human disease pulmonary alveolar proteinosis (PAP). Previous metabolic studies in GM-CSF-deficient [GM(−/−)] mice indicated that defects in surfactant clearance cause the surfactant accumulation in PAP. In the present study, GM(−/−) mice were treated daily or weekly with recombinant mouse GM-CSF by aerosol inhalation or intraperitoneal injection for 4–5 wk. Lung histology, alveolar macrophage differentiation, and surfactant protein B immunostaining returned toward normal levels in the GM-CSF aerosol-treated mice. Alveolar and lung tissue saturated phosphatidylcholine and surfactant protein B concentrations were significantly decreased after treatment with aerosolized GM-CSF. Cessation of aerosolized GM-CSF for 5 wk resulted in increased saturated phosphatidylcholine pool sizes that returned to pretreatment levels. In contrast, PAP did not improve in GM(−/−) mice treated daily for 5 wk with larger doses of systemic GM-CSF. Aerosolized GM-CSF improved PAP in the GM(−/−) mice, demonstrating that surfactant homeostasis can be influenced by local administration of GM-CSF to the respiratory tract.
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McNiece, I., R. Andrews, M. Stewart, S. Clark, T. Boone, and P. Quesenberry. "Action of interleukin-3, G-CSF, and GM-CSF on highly enriched human hematopoietic progenitor cells: synergistic interaction of GM-CSF plus G-CSF." Blood 74, no. 1 (July 1, 1989): 110–14. http://dx.doi.org/10.1182/blood.v74.1.110.110.
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Abstract Purified preparations of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and interleukin 3 (IL-3 or multi-CSF) alone and in combination, have been compared for their stimulatory effects on human granulocyte-macrophage colony forming cells (GM-CFC). In cultures of unseparated normal human bone marrow, the combinations of G-CSF plus IL-3 and GM-CSF plus IL-3 stimulated additive numbers of GM colonies, while GM-CSF plus G-CSF stimulated greater than additive numbers of GM colonies, compared with the sum of the colony formation obtained with each factor alone. Cultures of unseparated bone marrow, harvested from patients four to six days after administration of 5-fluorouracil (5-FU), resulted in additive GM colony formation with GM-CSF plus G-CSF, GM-CSF plus IL-3, and G-CSF plus IL-3. In order to address the possibility of secondary factor involvement in the synergistic interaction of GM-CSF and G-CSF, CD33+/CD34+ colony forming cells were separated from normal and post FU marrow by two color fluorescence activated cell sorting. In cultures of CD33+/CD34+ cells the combination of GM-CSF plus G-CSF stimulated a synergistic increase in GM colonies while GM-CSF plus IL-3 stimulated additive numbers of colonies. These results suggest that GM-CSF, G-CSF, and IL-3 stimulate distinct populations of GM-CFC. Furthermore GM-CSF and G-CSF interact synergistically and this action is a direct effect on progenitor cells not stimulated by GM-CSF or G-CSF alone.
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McNiece, I., R. Andrews, M. Stewart, S. Clark, T. Boone, and P. Quesenberry. "Action of interleukin-3, G-CSF, and GM-CSF on highly enriched human hematopoietic progenitor cells: synergistic interaction of GM-CSF plus G-CSF." Blood 74, no. 1 (July 1, 1989): 110–14. http://dx.doi.org/10.1182/blood.v74.1.110.bloodjournal741110.
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Purified preparations of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte CSF (G-CSF), and interleukin 3 (IL-3 or multi-CSF) alone and in combination, have been compared for their stimulatory effects on human granulocyte-macrophage colony forming cells (GM-CFC). In cultures of unseparated normal human bone marrow, the combinations of G-CSF plus IL-3 and GM-CSF plus IL-3 stimulated additive numbers of GM colonies, while GM-CSF plus G-CSF stimulated greater than additive numbers of GM colonies, compared with the sum of the colony formation obtained with each factor alone. Cultures of unseparated bone marrow, harvested from patients four to six days after administration of 5-fluorouracil (5-FU), resulted in additive GM colony formation with GM-CSF plus G-CSF, GM-CSF plus IL-3, and G-CSF plus IL-3. In order to address the possibility of secondary factor involvement in the synergistic interaction of GM-CSF and G-CSF, CD33+/CD34+ colony forming cells were separated from normal and post FU marrow by two color fluorescence activated cell sorting. In cultures of CD33+/CD34+ cells the combination of GM-CSF plus G-CSF stimulated a synergistic increase in GM colonies while GM-CSF plus IL-3 stimulated additive numbers of colonies. These results suggest that GM-CSF, G-CSF, and IL-3 stimulate distinct populations of GM-CFC. Furthermore GM-CSF and G-CSF interact synergistically and this action is a direct effect on progenitor cells not stimulated by GM-CSF or G-CSF alone.
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Khanjari, F. "GM-CSF and proteinosis." Thorax 58, no. 7 (July 1, 2003): 645. http://dx.doi.org/10.1136/thorax.58.7.645.
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Papatriantafyllou, Maria. "GM-CSF in focus." Nature Reviews Immunology 11, no. 6 (May 20, 2011): 370–71. http://dx.doi.org/10.1038/nri2996.
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Gillis, Steven, and Leslie Garrison. "Antibodies to GM-CSF." Lancet 335, no. 8699 (May 1990): 1217. http://dx.doi.org/10.1016/0140-6736(90)92735-z.
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Middleton, M., and N. Thatcher. "G- and GM-CSF." International Journal of Antimicrobial Agents 10, no. 2 (May 1998): 91–93. http://dx.doi.org/10.1016/s0924-8579(98)00015-6.
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Mehta, Hrishikesh M., Michael Malandra, and Seth J. Corey. "G-CSF and GM-CSF in Neutropenia." Journal of Immunology 195, no. 4 (August 7, 2015): 1341–49. http://dx.doi.org/10.4049/jimmunol.1500861.
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Frossard, Jean Louis, Ashok K. Saluja, Nicolas Mach, Hong Sik Lee, Lakshmi Bhagat, Antoine Hadenque, Laura Rubbia-Brandt, Glenn Dranoff, and Michael L. Steer. "In vivo evidence for the role of GM-CSF as a mediator in acute pancreatitis-associated lung injury." American Journal of Physiology-Lung Cellular and Molecular Physiology 283, no. 3 (September 1, 2002): L541—L548. http://dx.doi.org/10.1152/ajplung.00413.2001.
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Severe pancreatitis is frequently associated with acute lung injury (ALI) and the respiratory distress syndrome. The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mediating the ALI associated with secretagogue-induced experimental pancreatitis was evaluated with GM-CSF knockout mice (GM-CSF −/−). Pancreatitis was induced by hourly (12×) intraperitoneal injection of a supramaximally stimulating dose of the cholecystokinin analog caerulein. The resulting pancreatitis was similar in GM-CSF-sufficient (GM-CSF +/+) control animals and GM-CSF −/− mice. Lung injury, quantitated by measuring lung myeloperoxidase activity (an indicator of neutrophil sequestration), alveolar-capillary permeability, and alveolar membrane thickness was less severe in GM-CSF −/− than in GM-CSF +/+ mice. In GM-CSF +/+ mice, pancreas, lung and serum GM-CSF levels increase during pancreatitis. Lung levels of macrophage inflammatory protein (MIP)-2 are also increased during pancreatitis, but, in this case, the rise is less profound in GM-CSF −/− mice than in GM-CSF +/+ controls. Administration of anti-MIP-2 antibodies was found to reduce the severity of pancreatitis-associated ALI. Our findings indicate that GM-CSF plays a critical role in coupling pancreatitis to ALI and suggest that GM-CSF may act indirectly by regulating the release of other proinflammatory factors including MIP-2.
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Campbell, Ian K., Melissa J. Rich, Robert J. Bischof, Ashley R. Dunn, Dianne Grail, and John A. Hamilton. "Protection from Collagen-Induced Arthritis in Granulocyte-Macrophage Colony-Stimulating Factor-Deficient Mice." Journal of Immunology 161, no. 7 (October 1, 1998): 3639–44. http://dx.doi.org/10.4049/jimmunol.161.7.3639.
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Abstract The involvement of granulocyte-macrophage CSF (GM-CSF) in collagen-induced arthritis (CIA) was examined using GM-CSF-deficient mice. Although CIA is generally considered to be restricted to mice of the H-2q or H-2r haplotypes, we examined the role of GM-CSF in the CIA model using GM-CSF-deficient (−/−) and wild-type (+/+) mice on a C57BL/6 (H-2b) background. Mice were immunized by intradermal injection at the base of the tail with chick type II collagen followed by a repeat injection 21 days later. We found, based on both clinical and histologic assessments, that wild-type mice on this background developed severe CIA, while the GM-CSF-deficient mice had virtually no disease. Mice that were heterozygous for the GM-CSF gene (+/−) collectively displayed an intermediate response between those of the GM-CSF+/+ and GM-CSF−/− groups, suggesting a gene dosage effect. GM-CSF+/+ and GM-CSF+/− mice exhibited CIA responses ranging from mild (single digits) to severe swelling of all four paws, while in the few GM-CSF−/− mice that developed CIA the disease was confined to single digits. Despite the putative role of GM-CSF in dendritic cell development, GM-CSF-deficient mice exhibited both humoral and cellular (delayed-type hypersensitivity) responses to type II collagen; however, the cellular response was significantly reduced in the GM-CSF-deficient mice compared with the wild-type controls. These findings suggest that GM-CSF is required for CIA development in mice and support the idea that GM-CSF is a key cytokine in inflammatory joint disease.
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Ballinger, Megan N., Leah L. N. Hubbard, Tracy R. McMillan, Galen B. Toews, Marc Peters-Golden, Robert Paine, and Bethany B. Moore. "Paradoxical role of alveolar macrophage-derived granulocyte-macrophage colony-stimulating factor in pulmonary host defense post-bone marrow transplantation." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 1 (July 2008): L114—L122. http://dx.doi.org/10.1152/ajplung.00309.2007.
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Impaired host defense post-bone marrow transplant (BMT) is related to overproduction of prostaglandin E2(PGE2) by alveolar macrophages (AMs). We show AMs post-BMT overproduce granulocyte-macrophage colony-stimulating factor (GM-CSF), whereas GM-CSF in lung homogenates is impaired both at baseline and in response to infection post-BMT. Homeostatic regulation of GM-CSF may occur by hematopoietic/structural cell cross talk. To determine whether AM overproduction of GM-CSF influenced immunosuppression post-BMT, we compared mice that received BMT from wild-type donors (control BMT) or mice that received BMT from GM-CSF−/− donors (GM-CSF−/− BMT) with untransplanted mice. GM-CSF−/− BMT mice were less susceptible to pneumonia with Pseudomonas aeruginosa compared with control BMT mice and showed antibacterial responses equal to or better than untransplanted mice. GM-CSF−/− BMT AMs displayed normal phagocytosis and a trend toward enhanced bacterial killing. Surprisingly, AMs from GM-CSF−/− BMT mice overproduced PGE2, but expression of the inhibitory EP2receptor was diminished. As a consequence of decreased EP2receptor expression, we found diminished accumulation of cAMP in response to PGE2stimulation in GM-CSF−/− BMT AMs compared with control BMT AMs. In addition, GM-CSF−/− BMT AMs retained cysteinyl leukotriene production and normal TNF-α response compared with AMs from control BMT mice. GM-CSF−/− BMT neutrophils also showed improved bacterial killing. Although genetic ablation of GM-CSF in hematopoietic cells post-BMT improved host defense, transplantation of wild-type bone marrow into GM-CSF−/− recipients demonstrated that parenchymal cell-derived GM-CSF is necessary for effective innate immune responses post-BMT. These results highlight the complex regulation of GM-CSF and innate immunity post-BMT.
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Lieschke, GJ, E. Stanley, D. Grail, G. Hodgson, V. Sinickas, JA Gall, RA Sinclair, and AR Dunn. "Mice lacking both macrophage- and granulocyte-macrophage colony- stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease." Blood 84, no. 1 (July 1, 1994): 27–35. http://dx.doi.org/10.1182/blood.v84.1.27.27.
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Abstract Mice deficient in granulocyte-macrophage colony-stimulating factor (GM- CSF) and macrophage colony-stimulating factor (M-CSF, CSF-1) were generated by interbreeding GM-CSF-deficient mice generated by gene targeting (genotype GM-/-) with M-CSF-deficient osteopetrotic mice (genotype M-/-, op/op). Mice deficient in both GM-CSF and M-CSF (genotype GM-/-M-/-) are viable and have coexistent features corresponding to mice deficient in either factor alone. Like M-CSF- deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption. Like GM-CSF-deficient mice, they have a characteristic alveolar-proteinosis-like lung pathology, but it is more severe than that of GM-CSF-deficient mice and is often fatal. In particular, in GM-/-M-/- mice the accumulation of lipo-proteinaceous alveolar material is more marked, and bacterial pneumonic infections are more prevalent and more extensive, particularly involving Gram- negative bacteria. Neutrophilia consistently accompanies pulmonary infections, and some older GM-/-M-/- mice have polycythemia. Survival of GM-/-M-/- mice is significantly reduced compared with mice deficient in either factor alone, and all GM-/-M-/- mice have broncho- or lobar- pneumonia at death. These observations indicate that in vivo, M-CSF is involved in modulating the consequences of GM-CSF deficiency in the lung. Interestingly, GM-/-M-/- mice have circulating monocytes at levels comparable with those in M-CSF-deficient mice and the diseased lungs of all GM-/-M-/- mice contain numerous phagocytically active macrophages, indicating that in addition to GM-CSF and M-CSF, other factors can be used for macrophage production and function in vivo.
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Lieschke, GJ, E. Stanley, D. Grail, G. Hodgson, V. Sinickas, JA Gall, RA Sinclair, and AR Dunn. "Mice lacking both macrophage- and granulocyte-macrophage colony- stimulating factor have macrophages and coexistent osteopetrosis and severe lung disease." Blood 84, no. 1 (July 1, 1994): 27–35. http://dx.doi.org/10.1182/blood.v84.1.27.bloodjournal84127.
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Mice deficient in granulocyte-macrophage colony-stimulating factor (GM- CSF) and macrophage colony-stimulating factor (M-CSF, CSF-1) were generated by interbreeding GM-CSF-deficient mice generated by gene targeting (genotype GM-/-) with M-CSF-deficient osteopetrotic mice (genotype M-/-, op/op). Mice deficient in both GM-CSF and M-CSF (genotype GM-/-M-/-) are viable and have coexistent features corresponding to mice deficient in either factor alone. Like M-CSF- deficient mice, they have osteopetrosis and are toothless because of failure of incisor eruption. Like GM-CSF-deficient mice, they have a characteristic alveolar-proteinosis-like lung pathology, but it is more severe than that of GM-CSF-deficient mice and is often fatal. In particular, in GM-/-M-/- mice the accumulation of lipo-proteinaceous alveolar material is more marked, and bacterial pneumonic infections are more prevalent and more extensive, particularly involving Gram- negative bacteria. Neutrophilia consistently accompanies pulmonary infections, and some older GM-/-M-/- mice have polycythemia. Survival of GM-/-M-/- mice is significantly reduced compared with mice deficient in either factor alone, and all GM-/-M-/- mice have broncho- or lobar- pneumonia at death. These observations indicate that in vivo, M-CSF is involved in modulating the consequences of GM-CSF deficiency in the lung. Interestingly, GM-/-M-/- mice have circulating monocytes at levels comparable with those in M-CSF-deficient mice and the diseased lungs of all GM-/-M-/- mice contain numerous phagocytically active macrophages, indicating that in addition to GM-CSF and M-CSF, other factors can be used for macrophage production and function in vivo.
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Osborne, C. S., M. A. Vadas, and P. N. Cockerill. "Transcriptional regulation of mouse granulocyte-macrophage colony-stimulating factor/IL-3 locus." Journal of Immunology 155, no. 1 (July 1, 1995): 226–35. http://dx.doi.org/10.4049/jimmunol.155.1.226.
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Abstract Granulocyte-macrophage (GM)-CSF and IL-3 are hemopoietic growth factors whose genes are closely linked in both humans and mice. In humans, the GM-CSF and IL-3 genes are regulated by a cyclosporin A-inhibitable enhancer located 3 kb upstream of the GM-CSF gene that is inducible by signals that mimic TCR activation. To search for a murine homologue of this enhancer we probed mouse genomic DNA and located a 400-bp element 2 kb upstream of the mouse GM-CSF gene that was 76% homologous with the human GM-CSF enhancer. Like the human GM-CSF enhancer, this element formed a cyclosporin A-inhibitable DNase I-hypersensitive site in the murine T cell line EL4 upon activation with phorbol ester and calcium ionophore. Transient transfection assays showed that this homologue of the human enhancer acted as an inducible enhancer of the thymidine kinase promoter, the mouse IL-3 promoter, and the human GM-CSF promoter. We observed, however, that the mouse GM-CSF promoter was significantly more active than the human GM-CSF promoter and found that it supported a level of activity equivalent to the combination of the human GM-CSF promoter and the human GM-CSF enhancer. Consequently, the activity of mouse GM-CSF promoter was not significantly elevated in the presence of the mouse GM-CSF enhancer. Because the mouse GM-CSF enhancer is considerably less active than its human homologue we suggest that the mouse GM-CSF gene has evolved with less dependence upon the upstream enhancer for its activation.
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Rothstein, G., SM Rhondeau, CA Peters, RD Christensen, D. Lynch, and S. Gillis. "Stimulation of neutrophil production in CSF-1-responsive clones." Blood 72, no. 3 (September 1, 1988): 898–902. http://dx.doi.org/10.1182/blood.v72.3.898.898.
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Abstract The hematopoietic growth factor CSF-1 has been considered relatively lineage specific for the production of macrophages, whereas GM-CSF elicits a predominance of neutrophils. It is likely that in vivo, individual clones are stimulated by the two CSFs, although the effect of dual stimulation on progenitors and their progeny has not been completely explored. We found that in cultures initiated with low concentrations of CSF-1 or GM-CSF, alone or in combination, production of macrophages predominated. Maximally stimulatory concentrations of CSF-1 elicited a predominance of macrophages, whereas maximal GM-CSF elicited many more neutrophil/macrophage colonies and pure neutrophil colonies. A combination of maximal CSF-1 and GM-CSF elicited the same differentiation as GM-CSF alone. Delayed addition of GM-CSF to cultures initiated with CSF-1 elicited colonies indistinguishable from GM-CSF alone, suggesting that neutrophil production had been switched on by GM- CSF. In mapping studies, colonies initiated by CSF-1 increased or switched on neutrophil production when GM-CSF was added as a second stimulus. These studies show that individual clones are responsive to both CSFs, and that the differentiating influence of GM-CSF predominates over that of CSF-1. In cultures to which only CSF-1 was added, a population of progenitors was sustained that produced neutrophils only after a GM-CSF stimulus. Thus, CSF-1 may participate in maintaining a reserve of progenitors for neutrophils during periods of increased neutrophil demand.
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Rothstein, G., SM Rhondeau, CA Peters, RD Christensen, D. Lynch, and S. Gillis. "Stimulation of neutrophil production in CSF-1-responsive clones." Blood 72, no. 3 (September 1, 1988): 898–902. http://dx.doi.org/10.1182/blood.v72.3.898.bloodjournal723898.
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The hematopoietic growth factor CSF-1 has been considered relatively lineage specific for the production of macrophages, whereas GM-CSF elicits a predominance of neutrophils. It is likely that in vivo, individual clones are stimulated by the two CSFs, although the effect of dual stimulation on progenitors and their progeny has not been completely explored. We found that in cultures initiated with low concentrations of CSF-1 or GM-CSF, alone or in combination, production of macrophages predominated. Maximally stimulatory concentrations of CSF-1 elicited a predominance of macrophages, whereas maximal GM-CSF elicited many more neutrophil/macrophage colonies and pure neutrophil colonies. A combination of maximal CSF-1 and GM-CSF elicited the same differentiation as GM-CSF alone. Delayed addition of GM-CSF to cultures initiated with CSF-1 elicited colonies indistinguishable from GM-CSF alone, suggesting that neutrophil production had been switched on by GM- CSF. In mapping studies, colonies initiated by CSF-1 increased or switched on neutrophil production when GM-CSF was added as a second stimulus. These studies show that individual clones are responsive to both CSFs, and that the differentiating influence of GM-CSF predominates over that of CSF-1. In cultures to which only CSF-1 was added, a population of progenitors was sustained that produced neutrophils only after a GM-CSF stimulus. Thus, CSF-1 may participate in maintaining a reserve of progenitors for neutrophils during periods of increased neutrophil demand.
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Wognum, AW, Y. Westerman, TP Visser, and G. Wagemaker. "Distribution of receptors for granulocyte-macrophage colony-stimulating factor on immature CD34+ bone marrow cells, differentiating monomyeloid progenitors, and mature blood cell subsets." Blood 84, no. 3 (August 1, 1994): 764–74. http://dx.doi.org/10.1182/blood.v84.3.764.764.
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Abstract Biotin-labeled granulocyte-macrophage colony-stimulating factor (GM- CSF), in combination with phycoerythrin-conjugated streptavidin, enabled flow cytometric analysis of specific cell-surface GM-CSF receptors on rhesus monkey bone marrow (BM) and peripheral blood (PB) cells. GM-CSF receptors were readily detected on PB monocytes and neutrophils, but not on lymphocytes. In BM, GM-CSF receptors were identified on monocyte and neutrophil precursors and on subsets of cells that expressed the CD34 antigen. CD34+ cells with high GM-CSF- receptor expression coexpressed high levels of the class II major histocompatibility antigen RhLA-DR, whereas CD34+/RhLA-DRlow cells, which represent developmentally earlier cells, were either GM-CSF- receptor negative or expressed GM-CSF receptors at very low levels. The fluorescence histogram of CD34bright/RhLA-DRdull cells stained with biotin-GM-CSF showed that at least a fraction of these cells expressed low levels of GM-CSF receptors. CD34+ cells with high GM-CSF-receptor expression, purified by cell sorting, did not form colonies in culture or proliferate in response to GM-CSF. Instead, GM-CSF stimulation resulted in terminal differentiation into adherent cells, showing that these cells represented monocyte precursors. A distinct subset of CD34+ cells expressed GM-CSF receptors at low-to-intermediate levels and proliferated strongly in the presence of GM-CSF during short-term culture, but produced very few erythroid or monomyeloid colonies after longer culture periods. Most colony-forming cells, also those responsive to GM-CSF alone, were recovered in the subset of CD34+ cells on which GM-CSF receptors were virtually undetectable. These cells showed weaker proliferation in short-term proliferation assays than the CD34+/GM-CSF-receptor-intermediate cells, consistent with an immature phenotype. The results show that GM-CSF-receptor expression is initiated in a subset of immature, CD34bright/RhLA-DRdull cells and is progressively increased during differentiation into mature granulocytes and monocytes. The method used provides a new way to deplete developmentally early CD34+ cell of differentiating granulocyte and monocyte precursor cells.
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Wognum, AW, Y. Westerman, TP Visser, and G. Wagemaker. "Distribution of receptors for granulocyte-macrophage colony-stimulating factor on immature CD34+ bone marrow cells, differentiating monomyeloid progenitors, and mature blood cell subsets." Blood 84, no. 3 (August 1, 1994): 764–74. http://dx.doi.org/10.1182/blood.v84.3.764.bloodjournal843764.
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Biotin-labeled granulocyte-macrophage colony-stimulating factor (GM- CSF), in combination with phycoerythrin-conjugated streptavidin, enabled flow cytometric analysis of specific cell-surface GM-CSF receptors on rhesus monkey bone marrow (BM) and peripheral blood (PB) cells. GM-CSF receptors were readily detected on PB monocytes and neutrophils, but not on lymphocytes. In BM, GM-CSF receptors were identified on monocyte and neutrophil precursors and on subsets of cells that expressed the CD34 antigen. CD34+ cells with high GM-CSF- receptor expression coexpressed high levels of the class II major histocompatibility antigen RhLA-DR, whereas CD34+/RhLA-DRlow cells, which represent developmentally earlier cells, were either GM-CSF- receptor negative or expressed GM-CSF receptors at very low levels. The fluorescence histogram of CD34bright/RhLA-DRdull cells stained with biotin-GM-CSF showed that at least a fraction of these cells expressed low levels of GM-CSF receptors. CD34+ cells with high GM-CSF-receptor expression, purified by cell sorting, did not form colonies in culture or proliferate in response to GM-CSF. Instead, GM-CSF stimulation resulted in terminal differentiation into adherent cells, showing that these cells represented monocyte precursors. A distinct subset of CD34+ cells expressed GM-CSF receptors at low-to-intermediate levels and proliferated strongly in the presence of GM-CSF during short-term culture, but produced very few erythroid or monomyeloid colonies after longer culture periods. Most colony-forming cells, also those responsive to GM-CSF alone, were recovered in the subset of CD34+ cells on which GM-CSF receptors were virtually undetectable. These cells showed weaker proliferation in short-term proliferation assays than the CD34+/GM-CSF-receptor-intermediate cells, consistent with an immature phenotype. The results show that GM-CSF-receptor expression is initiated in a subset of immature, CD34bright/RhLA-DRdull cells and is progressively increased during differentiation into mature granulocytes and monocytes. The method used provides a new way to deplete developmentally early CD34+ cell of differentiating granulocyte and monocyte precursor cells.
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Nimer, S. D., M. J. Gates, H. P. Koeffler, and J. C. Gasson. "Multiple mechanisms control the expression of granulocyte-macrophage colony-stimulating factor by human fibroblasts." Journal of Immunology 143, no. 7 (October 1, 1989): 2374–77. http://dx.doi.org/10.4049/jimmunol.143.7.2374.
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Abstract Human granulocyte-macrophage colony-stimulating factor (GM-CSF) has in vitro and in vivo effects on hemopoiesis and enhances the function of circulating mature myeloid cells. Unstimulated fibroblasts show low level GM-CSF transcription but no accumulation of GM-CSF mRNA or protein, whereas fibroblasts stimulated by TNF-alpha, IL-1, and phorbol diester have been shown to produce and secrete GM-CSF. To determine the mechanisms controlling the expression of GM-CSF in human fibroblasts, we used a transient transfection assay to look at the effect of TNF-alpha, IL-1 and phorbol diester on GM-CSF promoter sequences. Our results demonstrate that the phorbol diester, 12-O-tetradecanoylphorbol 13-acetate, can stimulate GM-CSF transcription via sequences located within 53 bp upstream of the GM-CSF cap site. TNF-alpha and IL-1 had no effect on GM-CSF transcription, suggesting that these cytokines act predominantly post-transcriptionally to stimulate production of GM-CSF. Our results demonstrate that multiple mechanisms can be used by human fibroblasts to produce GM-CSF in response to various inflammatory stimuli.
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Kanakura, Y., SA Cannistra, CB Brown, M. Nakamura, GF Seelig, WW Prosise, JC Hawkins, K. Kaushansky, and JD Griffin. "Identification of functionally distinct domains of human granulocyte- macrophage colony-stimulating factor using monoclonal antibodies." Blood 77, no. 5 (March 1, 1991): 1033–43. http://dx.doi.org/10.1182/blood.v77.5.1033.1033.
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Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein that is required for the survival, growth, and differentiation of hematopoietic progenitor cells. Although the primary structure of GM-CSF is known from cDNA cloning, the relationship between structure and function of GM-CSF is not fully understood. Fifteen different monoclonal antibodies (MoAbs) to human GM-CSF were generated to map immunologically distinct areas of the molecule. Each of the MoAbs was biotinylated and shown by enzyme-linked immunosorbent assay to bind to recombinant GM-CSF that had been affixed to a solid phase. Each of the 15 unconjugated MoAbs was then used to compete with each biotinylated MoAb for binding to GM-CSF. These cross-blocking studies identified eight distinct epitopes of native GM-CSF. Seven of these epitopes were also present in denatured GM-CSF by Western blotting, and four of the epitopes were at least partially conserved on GM-CSF that was reduced in beta-mercaptoethanol. MoAbs to four of eight epitopes neutralized both recombinant (glycosylated and nonglycosylated) and natural human GM-CSF in a GM colony-forming unit (CFU-GM) assay and blocked GM-CSF-induced activation of neutrophils. For most of the antibodies there was a good correlation between neutralizing activity and the capacity to block binding of 125I-GM-CSF to neutrophils or blasts. Non-neutralizing antibodies to one epitope partially blocked binding of 125I-GM-CSF to neutrophils. None of the MoAbs neutralized interleukin-3, G-CSF, or M-CSF. The locations of seven of the epitopes could be partially mapped with regard to the amino acid structure by determining reactivity to GM-CSF synthetic peptides or to human-mouse chimeric GM-CSFs. The neutralizing antibodies were found to map to amino acids 40–77, 78–94, or 110–127. Thus, these MoAbs are useful to identify functional domains of GM-CSF and in identifying regions that are likely to be involved in receptor interaction.
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Kanakura, Y., SA Cannistra, CB Brown, M. Nakamura, GF Seelig, WW Prosise, JC Hawkins, K. Kaushansky, and JD Griffin. "Identification of functionally distinct domains of human granulocyte- macrophage colony-stimulating factor using monoclonal antibodies." Blood 77, no. 5 (March 1, 1991): 1033–43. http://dx.doi.org/10.1182/blood.v77.5.1033.bloodjournal7751033.
Full textAbstract:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a glycoprotein that is required for the survival, growth, and differentiation of hematopoietic progenitor cells. Although the primary structure of GM-CSF is known from cDNA cloning, the relationship between structure and function of GM-CSF is not fully understood. Fifteen different monoclonal antibodies (MoAbs) to human GM-CSF were generated to map immunologically distinct areas of the molecule. Each of the MoAbs was biotinylated and shown by enzyme-linked immunosorbent assay to bind to recombinant GM-CSF that had been affixed to a solid phase. Each of the 15 unconjugated MoAbs was then used to compete with each biotinylated MoAb for binding to GM-CSF. These cross-blocking studies identified eight distinct epitopes of native GM-CSF. Seven of these epitopes were also present in denatured GM-CSF by Western blotting, and four of the epitopes were at least partially conserved on GM-CSF that was reduced in beta-mercaptoethanol. MoAbs to four of eight epitopes neutralized both recombinant (glycosylated and nonglycosylated) and natural human GM-CSF in a GM colony-forming unit (CFU-GM) assay and blocked GM-CSF-induced activation of neutrophils. For most of the antibodies there was a good correlation between neutralizing activity and the capacity to block binding of 125I-GM-CSF to neutrophils or blasts. Non-neutralizing antibodies to one epitope partially blocked binding of 125I-GM-CSF to neutrophils. None of the MoAbs neutralized interleukin-3, G-CSF, or M-CSF. The locations of seven of the epitopes could be partially mapped with regard to the amino acid structure by determining reactivity to GM-CSF synthetic peptides or to human-mouse chimeric GM-CSFs. The neutralizing antibodies were found to map to amino acids 40–77, 78–94, or 110–127. Thus, these MoAbs are useful to identify functional domains of GM-CSF and in identifying regions that are likely to be involved in receptor interaction.
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Suzuki, Takuji, Takuro Sakagami, Bruce K. Rubin, Lawrence M. Nogee, Robert E. Wood, Sarah L. Zimmerman, Teresa Smolarek, et al. "Familial pulmonary alveolar proteinosis caused by mutations in CSF2RA." Journal of Experimental Medicine 205, no. 12 (October 27, 2008): 2703–10. http://dx.doi.org/10.1084/jem.20080990.
Full textAbstract:
Primary pulmonary alveolar proteinosis (PAP) is a rare syndrome characterized by accumulation of surfactant in the lungs that is presumed to be mediated by disruption of granulocyte/macrophage colony-stimulating factor (GM-CSF) signaling based on studies in genetically modified mice. The effects of GM-CSF are mediated by heterologous receptors composed of GM-CSF binding (GM-CSF-Rα) and nonbinding affinity-enhancing (GM-CSF-Rβ) subunits. We describe PAP, failure to thrive, and increased GM-CSF levels in two sisters aged 6 and 8 yr with abnormalities of both GM-CSF-Rα–encoding alleles (CSF2RA). One was a 1.6-Mb deletion in the pseudoautosomal region of one maternal X chromosome encompassing CSF2RA. The other, a point mutation in the paternal X chromosome allele encoding a G174R substitution, altered an N-linked glycosylation site within the cytokine binding domain and glycosylation of GM-CSF-Rα, severely reducing GM-CSF binding, receptor signaling, and GM-CSF–dependent functions in primary myeloid cells. Transfection of cloned cDNAs faithfully reproduced the signaling defect at physiological GM-CSF concentrations. Interestingly, at high GM-CSF concentrations similar to those observed in the index patient, signaling was partially rescued, thereby providing a molecular explanation for the slow progression of disease in these children. These results establish that GM-CSF signaling is critical for surfactant homeostasis in humans and demonstrate that mutations in CSF2RA cause familial PAP.
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Ullenhag, G., C. Bird, P. Ragnhammar, J.-E. Frödin, K. Strigård, A. Österborg, R. Thorpe, H. Mellstedt, and M. Wadhwa. "Incidence of GM-CSF Antibodies in Cancer Patients Receiving GM-CSF for Immunostimulation." Clinical Immunology 99, no. 1 (April 2001): 65–74. http://dx.doi.org/10.1006/clim.2000.4999.
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Brizzi, Maria F., Carlo Arduino, G. Carlo Avanzi, Federico Bussolino, and Luigi Pegoraro. "GM-CSF and phorbol esters modulate GM-CSF receptor expression by independent mechanisms." Journal of Cellular Physiology 148, no. 1 (July 1991): 24–34. http://dx.doi.org/10.1002/jcp.1041480104.
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Weisdorf, DJ, CM Verfaillie, SM Davies, AH Filipovich, JE Jr Wagner, JS Miller, J. Burroughs, NK Ramsay, JH Kersey, and PB McGlave. "Hematopoietic growth factors for graft failure after bone marrow transplantation: a randomized trial of granulocyte-macrophage colony- stimulating factor (GM-CSF) versus sequential GM-CSF plus granulocyte- CSF." Blood 85, no. 12 (June 15, 1995): 3452–56. http://dx.doi.org/10.1182/blood.v85.12.3452.bloodjournal85123452.
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Delay in hematologic recovery after bone marrow transplantation (BMT) can extend and amplify the risks of infection and hemorrhage, compromise patients' survival, and increase the duration and cost of hospitalization. Because current studies suggest that granulocyte-macrophage (GM) colony-stimulating factor (CSF) may potentiate the sensitivity of hematopoietic progenitor cells to G-CSF, we performed a prospective, randomized trial comparing GM-CSF (250 micrograms/m2/d x 14 days) versus sequential GM-CSF x 7 days followed by G-CSF (5 micrograms/kg/d x 7 days) as treatment for primary or secondary graft failure after BMT. Eligibility criteria included failure to achieve a white blood cell (WBC) count > or = 100/microL by day +21 or > or = 300/microL by day +28, no absolute neutrophil count (ANC) > or = 200/microL by day +28, or secondary sustained neutropenia after initial engraftment. Forty-seven patients were enrolled: 23 received GM-CSF (10 unrelated, 8 related allogeneic, and 5 autologous), and 24 received GM-CSF followed by G-CSF (12 unrelated, 7 related allogeneic, and 5 autologous). For patients receiving GM-CSF alone, neutrophil recovery (ANC > or = 500/microL) occurred between 2 and 61 days (median, 8 days) after therapy, while those receiving GM-CSF+G-CSF recovered at a similar rate of 1 to 36 days (median, 6 days; P = .39). Recovery to red blood cell (RBC) transfusion independence was slow, occurring 6 to 250 days (median, 35 days) after enrollment with no significant difference between the two treatment groups (GM-CSF: median, 30 days; GM-CSF+G-CSF; median, 42 days; P = .24). Similarly, platelet transfusion independence was delayed until 4 to 249 days (median, 32 days) after enrollment, with no difference between the two treatment groups (GM-CSF: median, 28 days; GM-CSF+G-CSF: median, 42 days; P = .38). Recovery times were not different between patients with unrelated donors and those with related donors or autologous transplant recipients. Survival at 100 days after enrollment was superior after treatment with GM-CSF alone. Only 1 of 23 patients treated with GM-CSF died versus 7 of 24 treated with GM-CSF+G-CSF who died 16 to 84 days (median, 38 days) after enrollment, yielding Kaplan-Meier 100-day survival estimates of 96% +/- 8% for GM-CSF versus 71% +/- 18% for GM-CSF+G-CSF (P = .026). These data suggest that sequential growth factor therapy with GM-CSF followed by G-CSF offers no advantage over GM-CSF alone in accelerating trilineage hematopoiesis or preventing lethal complications in patients with poor graft function after BMT.(ABSTRACT TRUNCATED AT 400 WORDS)
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Stewart-Akers, AM, JS Cairns, DJ Tweardy, and SA McCarthy. "Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation." Blood 83, no. 3 (February 1, 1994): 713–23. http://dx.doi.org/10.1182/blood.v83.3.713.713.
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Abstract The effects of granulocyte-macrophage colony-stimulating factor (GM- CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T- cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM- CSF responsive cell type, thymic AC and T cells were examined for GM- CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single- cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.
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Stewart-Akers, AM, JS Cairns, DJ Tweardy, and SA McCarthy. "Granulocyte-macrophage colony-stimulating factor augmentation of T-cell receptor-dependent and T-cell receptor-independent thymocyte proliferation." Blood 83, no. 3 (February 1, 1994): 713–23. http://dx.doi.org/10.1182/blood.v83.3.713.bloodjournal833713.
Full textAbstract:
The effects of granulocyte-macrophage colony-stimulating factor (GM- CSF) are not confined to cells of the myeloid lineage. GM-CSF has been shown to have effects on mature T cells and both mature and immature T- cell lines. We therefore examined the GM-CSF responsiveness of murine thymocytes to investigate whether GM-CSF also affected normal immature T lymphocytes. The studies presented here indicate that GM-CSF augments accessory cell (AC)-dependent T-cell receptor (TCR)-mediated proliferation of unseparated thymocyte populations. To identify the GM- CSF responsive cell type, thymic AC and T cells were examined for GM- CSF responsiveness. We found that GM-CSF augmentation of TCR-induced thymocyte proliferation appears to be mediated via augmentation of AC function, and not via direct effects on mature single-positive (SP) thymocytes. Enriched double-negative (DN) thymocytes were also tested for GM-CSF responsiveness. GM-CSF induced the proliferation of adult and fetal DN thymocytes in an AC-independent and TCR-independent single- cell assay. Thus, in contrast to the SP thymocytes, a DN thymocyte population was directly responsive to GM-CSF. GM-CSF therefore may play a direct role in the expansion of DN thymocytes and an indirect role in the expansion of SP thymocytes.
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Metcalf, Donald, Nicos A. Nicola, Sandra Mifsud, and Ladina Di Rago. "Receptor Clearance Obscures the Magnitude of Granulocyte-Macrophage Colony-Stimulating Factor Responses in Mice to Endotoxin or Local Infections." Blood 93, no. 5 (March 1, 1999): 1579–85. http://dx.doi.org/10.1182/blood.v93.5.1579.
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Abstract Marrow cells from mice lacking high-affinity receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF; βc−/− mice) were shown to bind and internalize much less GM-CSF than cells from normal (βc+/+) mice. βc−/− mice were used to determine the effect of negligible receptor-mediated clearance on detectible GM-CSF responses to the intravenous injection of endotoxin or the intraperitoneal injection of casein plus microorganisms. Unlike the minor serum GM-CSF responses to endotoxin seen in βc+/+ mice, serum GM-CSF levels rose 30-fold to 9 ng/mL in βc−/− mice even though loss of GM-CSF in the urine was greater than in βc+/+ mice. Organs from βc−/− and βc+/+ mice had a similar capacity to produce GM-CSF in vitro, as did peritoneal cells from both types of mice when challenged in vitro by casein. However, when casein was injected intraperitoneally, βc−/− mice developed higher and more sustained levels of GM-CSF than did βc+/+ mice. The data indicated that receptor-dependent removal of GM-CSF masks the magnitude of GM-CSF responses to endotoxin and local infections. Because of this phenomenon, serum GM-CSF concentrations can be a misleading index of the occurrence or nonoccurrence of GM-CSF responses to infections.
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Metcalf, Donald, Nicos A. Nicola, Sandra Mifsud, and Ladina Di Rago. "Receptor Clearance Obscures the Magnitude of Granulocyte-Macrophage Colony-Stimulating Factor Responses in Mice to Endotoxin or Local Infections." Blood 93, no. 5 (March 1, 1999): 1579–85. http://dx.doi.org/10.1182/blood.v93.5.1579.405k01_1579_1585.
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Marrow cells from mice lacking high-affinity receptors for granulocyte-macrophage colony-stimulating factor (GM-CSF; βc−/− mice) were shown to bind and internalize much less GM-CSF than cells from normal (βc+/+) mice. βc−/− mice were used to determine the effect of negligible receptor-mediated clearance on detectible GM-CSF responses to the intravenous injection of endotoxin or the intraperitoneal injection of casein plus microorganisms. Unlike the minor serum GM-CSF responses to endotoxin seen in βc+/+ mice, serum GM-CSF levels rose 30-fold to 9 ng/mL in βc−/− mice even though loss of GM-CSF in the urine was greater than in βc+/+ mice. Organs from βc−/− and βc+/+ mice had a similar capacity to produce GM-CSF in vitro, as did peritoneal cells from both types of mice when challenged in vitro by casein. However, when casein was injected intraperitoneally, βc−/− mice developed higher and more sustained levels of GM-CSF than did βc+/+ mice. The data indicated that receptor-dependent removal of GM-CSF masks the magnitude of GM-CSF responses to endotoxin and local infections. Because of this phenomenon, serum GM-CSF concentrations can be a misleading index of the occurrence or nonoccurrence of GM-CSF responses to infections.
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Freedman, MH, T. Grunberger, P. Correa, AA Axelrad, ID Dube, and A. Cohen. "Autocrine and paracrine growth control by granulocyte-monocyte colony- stimulating factor of acute lymphoblastic leukemia cells." Blood 81, no. 11 (June 1, 1993): 3068–75. http://dx.doi.org/10.1182/blood.v81.11.3068.3068.
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Abstract Blast colony assays were performed on freshly obtained bone marrow samples from 19 newly diagnosed or relapsed children with acute lymphoblastic leukemia (ALL) of B lineage to determine the effect of added granulocyte-monocyte colony-stimulating factor (GM-CSF). Of the 19 marrow samples tested, 7 responded to GM-CSF with a mean increase in ALL blast colonies of 346%. Blast cells from one of the responders chosen for flow cytometric study showed expression of GM-CSF receptors on 38% of cells. These findings prompted us to establish five ALL cell lines of diverse phenotypes to examine the expression of GM-CSF and GM- CSF receptor genes in human leukemia, and to determine the role of GM- CSF in autocrine and paracrine growth control of ALL cells. One line, termed G2, manifested a GM-CSF-mediated autocrine pattern of cell growth with the following features: G2 blast colony growth in a serum- free system without added growth factor was density dependent; exogenous GM-CSF augmented G2 colony formation when the cells were seeded at low density; G2 cells constitutively expressed mRNA for GM- CSF and GM-CSF receptor; G2 cells also produced and secreted measurable amounts of GM-CSF into cell culture supernatant; and, monoclonal anti- GM-CSF antibodies abolished G2 colony growth when added to cultures with cells seeded at low density without growth factors. Of the other four ALL cell lines, three expressed mRNA for GM-CSF receptor and responded in vitro to added GM-CSF with increased blast colony growth; however, none of these four cell lines expressed mRNA for constitutive production of GM-CSF. A fifth ALL cell line lacked receptors for GM-CSF and did not respond in clonogenic assays to added GM-CSF. Thus, a bioregulator of normal hematopoiesis plays a central role in autocrine growth control of G2 ALL cells, and an important paracrine growth- promoting role in three of four other ALL cell lines.
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Freedman, MH, T. Grunberger, P. Correa, AA Axelrad, ID Dube, and A. Cohen. "Autocrine and paracrine growth control by granulocyte-monocyte colony- stimulating factor of acute lymphoblastic leukemia cells." Blood 81, no. 11 (June 1, 1993): 3068–75. http://dx.doi.org/10.1182/blood.v81.11.3068.bloodjournal81113068.
Full textAbstract:
Blast colony assays were performed on freshly obtained bone marrow samples from 19 newly diagnosed or relapsed children with acute lymphoblastic leukemia (ALL) of B lineage to determine the effect of added granulocyte-monocyte colony-stimulating factor (GM-CSF). Of the 19 marrow samples tested, 7 responded to GM-CSF with a mean increase in ALL blast colonies of 346%. Blast cells from one of the responders chosen for flow cytometric study showed expression of GM-CSF receptors on 38% of cells. These findings prompted us to establish five ALL cell lines of diverse phenotypes to examine the expression of GM-CSF and GM- CSF receptor genes in human leukemia, and to determine the role of GM- CSF in autocrine and paracrine growth control of ALL cells. One line, termed G2, manifested a GM-CSF-mediated autocrine pattern of cell growth with the following features: G2 blast colony growth in a serum- free system without added growth factor was density dependent; exogenous GM-CSF augmented G2 colony formation when the cells were seeded at low density; G2 cells constitutively expressed mRNA for GM- CSF and GM-CSF receptor; G2 cells also produced and secreted measurable amounts of GM-CSF into cell culture supernatant; and, monoclonal anti- GM-CSF antibodies abolished G2 colony growth when added to cultures with cells seeded at low density without growth factors. Of the other four ALL cell lines, three expressed mRNA for GM-CSF receptor and responded in vitro to added GM-CSF with increased blast colony growth; however, none of these four cell lines expressed mRNA for constitutive production of GM-CSF. A fifth ALL cell line lacked receptors for GM-CSF and did not respond in clonogenic assays to added GM-CSF. Thus, a bioregulator of normal hematopoiesis plays a central role in autocrine growth control of G2 ALL cells, and an important paracrine growth- promoting role in three of four other ALL cell lines.
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Berclaz, Pierre-Yves, Yoko Shibata, Jeffrey A. Whitsett, and Bruce C. Trapnell. "GM-CSF, via PU.1, regulates alveolar macrophage FcγR-mediated phagocytosis and the IL-18/IFN-γ–mediated molecular connection between innate and adaptive immunity in the lung." Blood 100, no. 12 (December 1, 2002): 4193–200. http://dx.doi.org/10.1182/blood-2002-04-1102.
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Severely impaired pulmonary microbial clearance was observed in granulocyte-macrophage colony-stimulating factor (GM-CSF)–deficient mice. To determine mechanisms by which GM-CSF mediates lung host defense, FcγR-mediated phagocytosis (opsonophagocytosis) by alveolar macrophages (AMs) was assessed in GM-CSF–sufficient (GM+/+) and –deficient (GM−/−) mice and in GM−/− mice expressing GM-CSF only in the lungs from a surfactant protein C (SPC) promoter (SPC-GM+/+/GM−/−). Opsonophagocytosis by GM−/− AMs was severely impaired and was restored by pulmonary GM-CSF expression in vivo or by PU.1 expression in vitro. Defective opsonophagocytosis by GM−/− AMs was associated with decreased FcγR expression. Because interferon-γ (IFN-γ) augments macrophage FcγR levels, the role of GM-CSF/PU.1 in the regulation of AM FcγR expression by IFN-γ was assessed during adenoviral lung infection. Adenoviral infection stimulated IFN-γ production and augmented FcγR levels on AMs in GM-CSF–expressing but not GM−/− mice. However, IFN-γ exposure ex vivo stimulated FcγR expression on GM−/− AMs. Because interleukin-18 (IL-18) and IL-12 stimulate IFN-γ production during adenoviral infection, their role in GM-CSF/PU.1 regulation of IFN-γ–augmented FcγR expression on AMs was assessed. Adenoviral infection stimulated IL-18 and IL-12 production in GM-CSF–expressing mice, but both were markedly reduced or absent in GM−/−mice. IL-18 expression by GM−/− AMs was severely impaired and was restored by pulmonary GM-CSF expression in vivo or by PU.1 expression in vitro. Pulmonary administration of IL-18 in GM−/− mice stimulated IFN-γ production and restored FcγR expression on AMs. These results show that GM-CSF, via PU.1, regulates constitutive AM FcγR expression and opsonophagocytosis and is required for the IFN-γ–dependent regulation of AM FcγR expression, enabling AMs to release IL-18/IL-12 during lung infection.
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Chen, BD, CR Clark, and TH Chou. "Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor." Blood 71, no. 4 (April 1, 1988): 997–1002. http://dx.doi.org/10.1182/blood.v71.4.997.997.
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Abstract Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a specific humoral growth factor that stimulates both neutrophilic granulocyte and macrophage production by bone marrow hematopoietic progenitor cells. GM-CSF also stimulates the proliferation and clonal growth of both tissue macrophages and blood monocytes. Although at low concentrations GM-CSF was unable to support the long-term growth of tissue macrophages, it greatly enhanced their responsiveness to macrophage CSF (M-CSF, or CSF-1). This effect was also observed by treating macrophages with GM-CSF for a short time. GM-CSF did not compete with M-CSF for binding to M-CSF receptors nor was it inactivated by treatment with anti-M-CSF antiserum. Treatment of tissue macrophages with GM-CSF led to a rapid but transient downregulation of M-CSF receptors; prolonged incubation at 37 degrees C, however, resulted in a restoration and upregulation of M-CSF receptors. Identical effects were observed with both native or recombinant GM-CSF. This study suggests that GM-CSF regulates tissue macrophage production by two modes of action: (a) direct stimulation of macrophage proliferation, and (b) enhancement of their responsiveness to M-CSF.
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Chen, BD, CR Clark, and TH Chou. "Granulocyte/macrophage colony-stimulating factor stimulates monocyte and tissue macrophage proliferation and enhances their responsiveness to macrophage colony-stimulating factor." Blood 71, no. 4 (April 1, 1988): 997–1002. http://dx.doi.org/10.1182/blood.v71.4.997.bloodjournal714997.
Full textAbstract:
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a specific humoral growth factor that stimulates both neutrophilic granulocyte and macrophage production by bone marrow hematopoietic progenitor cells. GM-CSF also stimulates the proliferation and clonal growth of both tissue macrophages and blood monocytes. Although at low concentrations GM-CSF was unable to support the long-term growth of tissue macrophages, it greatly enhanced their responsiveness to macrophage CSF (M-CSF, or CSF-1). This effect was also observed by treating macrophages with GM-CSF for a short time. GM-CSF did not compete with M-CSF for binding to M-CSF receptors nor was it inactivated by treatment with anti-M-CSF antiserum. Treatment of tissue macrophages with GM-CSF led to a rapid but transient downregulation of M-CSF receptors; prolonged incubation at 37 degrees C, however, resulted in a restoration and upregulation of M-CSF receptors. Identical effects were observed with both native or recombinant GM-CSF. This study suggests that GM-CSF regulates tissue macrophage production by two modes of action: (a) direct stimulation of macrophage proliferation, and (b) enhancement of their responsiveness to M-CSF.
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Charbeneau, Ryan P., Paul J. Christensen, Cara J. Chrisman, Robert Paine, Galen B. Toews, Marc Peters-Golden, and Bethany B. Moore. "Impaired synthesis of prostaglandin E2 by lung fibroblasts and alveolar epithelial cells from GM-CSF−/− mice: implications for fibroproliferation." American Journal of Physiology-Lung Cellular and Molecular Physiology 284, no. 6 (June 1, 2003): L1103—L1111. http://dx.doi.org/10.1152/ajplung.00350.2002.
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Prostaglandin E2 (PGE2) is a potent suppressor of fibroblast activity. We previously reported that bleomycin-induced pulmonary fibrosis was exaggerated in granulocyte-macrophage colony-stimulating factor knockout (GM-CSF−/−) mice compared with wild-type (GM-CSF+/+) mice and that increased fibrosis was associated with decreased PGE2 levels in lung homogenates and alveolar macrophage cultures. Pulmonary fibroblasts and alveolar epithelial cells (AECs) represent additional cellular sources of PGE2 within the lung. Therefore, we examined fibroblasts and AECs from GM-CSF−/− mice, and we found that they elaborated significantly less PGE2 than did cells from GM-CSF+/+ mice. This defect was associated with reduced expression of cyclooxygenase-1 and -2 (COX-1 and COX-2), key enzymes in the biosynthesis of PGE2. Additionally, proliferation of GM-CSF−/− fibroblasts was greater than that of GM-CSF+/+ fibroblasts, and GM-CSF−/− AECs were impaired in their ability to inhibit fibroblast proliferation in coculture. The addition of GM-CSF to fibroblasts from GM-CSF−/− mice increased PGE2 production and decreased proliferation. Similarly, AECs isolated from GM-CSF−/− mice with transgenic expression of GM-CSF under the surfactant protein C promoter (SpC-GM mice) produced more PGE2 than did AEC from control mice. Finally, SpC-GM mice were protected from fluorescein isothiocyanate-induced pulmonary fibrosis. In conclusion, these data demonstrate that GM-CSF regulates PGE2 production in pulmonary fibroblasts and AECs and thus plays an important role in limiting fibroproliferation.
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Kassem, Neemat M., Alya M. Ayad, Noha M. El Husseiny, Doaa M. El-Demerdash, Hebatallah A. Kassem, and Mervat M. Mattar. "Role of Granulocyte-Macrophage Colony-Stimulating Factor in Acute Myeloid Leukemia/Myelodysplastic Syndromes." Journal of Global Oncology, no. 4 (December 2018): 1–6. http://dx.doi.org/10.1200/jgo.2017.009332.
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Purpose Granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine stimulates growth, differentiation, and function of myeloid progenitors. We aimed to study the role of GM-CSF gene expression, its protein, and antibodies in patients with acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) and their correlation to disease behavior and treatment outcome. The study included 50 Egyptian patients with AML/MDS in addition to 20 healthy volunteers as control subjects. Patients and Methods Assessment of GM-CSF gene expression was performed by quantitative real-time polymerase chain reaction. GM-CSF proteins and antibodies were assessed by enzyme-linked immunosorbent assay. Results There was significant decrease in GM-CSF gene expression ( P = .008), increase in serum level of GM-CSF protein ( P = .0001), and increase in anti–GM-CSF antibodies ( P = .001) in patients with AML/MDS compared with healthy control subjects. In addition, there was a significant negative correlation between serum levels of GM-CSF protein and initial peripheral blood blasts, percentage as well as response to therapy. Conclusion Any alteration in GM-CSF gene expression could have implications in leukemogenesis. In addition, GM-CSF protein serum levels could be used to predict outcome of therapy. GM-CSF antibodies may also play a role in the pathogenesis of AML/MDS. The use of these GM-CSF parameters for disease monitoring and as markers of disease activity needs further research.
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Chen, T. T., and R. Levy. "Induction of autoantibody responses to GM-CSF by hyperimmunization with an Id-GM-CSF fusion protein." Journal of Immunology 154, no. 7 (April 1, 1995): 3105–17. http://dx.doi.org/10.4049/jimmunol.154.7.3105.
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Abstract Fusion proteins consisting of an Ig containing xenogenic constant regions and granulocyte-macrophage colony stimulating factor (Id-GM-CSF) are potent immunogens capable of inducing anti-idiotypic Abs after two immunizations, without the usual need for adjuvants or carrier proteins. In this study, we investigated the effects of hyperimmunization with Id-GM-CSF and found that it induces anti-GM-CSF Abs that could bind to GM-CSF and neutralize its bioactivity in vitro. However, no detrimental effects of the anti-GM-CSF activity were apparent on the general health of the animals or on their base line white blood cell counts. Mice with the anti-GM-CSF activity reconstituted their peripheral white blood cells with identical kinetics as control mice after high dose cyclophosphamide treatment, sublethal irradiation, or lethal irradiation followed by syngeneic bone marrow transplantation. Primary and secondary Ab responses to a variety of protein Ags, including an unrelated Ig Id, were not affected. However, the anti-Id response induced by an unrelated GM-CSF fusion protein that is dependent upon the GM-CSF bioactivity was impaired. To avoid any potential problems associated with inducing anti-GM-CSF Abs, we show that priming with the Id-GM-CSF protein and boosting with the Id protein alone were sufficient to induce comparable anti-Id titers without inducing anti-GM-CSF Abs. We conclude that although hyperimmunization of mice with the GM-CSF fusion protein induced neutralizing anti-GM-CSF Abs, this was of little consequence to the animals. Nevertheless, we have devised a strategy to overcome this potential limitation on the use of GM-CSF fusion proteins for immunization.
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Nakata, K., K. S. Akagawa, M. Fukayama, Y. Hayashi, M. Kadokura, and T. Tokunaga. "Granulocyte-macrophage colony-stimulating factor promotes the proliferation of human alveolar macrophages in vitro." Journal of Immunology 147, no. 4 (August 15, 1991): 1266–72. http://dx.doi.org/10.4049/jimmunol.147.4.1266.
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Abstract The effects of granulocyte-macrophage (GM-CSF) or macrophage-CSF on in vitro proliferation of human alveolar macrophages (AM) were evaluated. AM of healthy volunteers incubated with recombinant human GM-CSF revealed incorporation of [3H]thymidine in vitro. The maximum incorporation was observed at 20 U/ml of GM-CSF on day 3. The proportion of proliferating cells incubated with 20 U/ml of GM-CSF from day 3 to day 4 was 8 to 11% of the total, whereas 3 to 5% of cells proliferated without GM-CSF. The number of cell nuclei increased 1.30- to 1.68-fold in the initial 7 days during incubation with 20 U/ml of GM-CSF, whereas there was a 1.07- to 1.13-fold increase without GM-CSF. Conditioned media obtained by the incubation with human lung tissue exhibited similar effects as recombinant human GM-CSF on macrophages. The effects were completely abrogated by antibody against human GM-CSF. Immunohistochemically, GM-CSF was detected in lung cells including AM, alveolar epithelium, alveolar interstitial cells, and endothelial cells. In contrast, recombinant macrophage-CSF did not induce the proliferation of human AM, although it has been known to promote the proliferation of murine AM. These observations suggest that GM-CSF plays an important role among the regulatory factors that locally support the population of AM in human lungs.
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Kitching, A. Richard, Xiao Ru Huang, Amanda L. Turner, Peter G. Tipping, Ashley R. Dunn, and Stephen R. Holdsworth. "The Requirement for Granulocyte-Macrophage Colony-Stimulating Factor and Granulocyte Colony-Stimulating Factor in Leukocyte-Mediated Immune Glomerular Injury." Journal of the American Society of Nephrology 13, no. 2 (February 2002): 350–58. http://dx.doi.org/10.1681/asn.v132350.
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ABSTRACT. Proliferative glomerulonephritis in humans is characterized by the presence of leukocytes in glomeruli. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and granulocyte colony-stimulating factor (G-CSF) can potentially stimulate or affect T cell, macrophage, and neutrophil function. To define the roles of GM-CSF and G-CSF in leukocyte-mediated glomerulonephritis, glomerular injury was studied in mice genetically deficient in either GM-CSF (GM-CSF −/− mice) or G-CSF (G-CSF −/− mice). Two models of glomerulonephritis were studied: neutrophil-mediated heterologous-phase anti-glomerular basement membrane (GBM) glomerulonephritis and T cell/macrophage-mediated crescentic autologous-phase anti-GBM glomerulonephritis. Both GM-CSF −/− and G-CSF −/− mice were protected from heterologous-phase anti-GBM glomerulonephritis compared with genetically normal (CSF WT) mice, with reduced proteinuria and glomerular neutrophil numbers. However, only GM-CSF −/− mice were protected from crescentic glomerular injury in the autologous phase, whereas G-CSF −/− mice were not protected and in fact had increased numbers of T cells in glomeruli. Humoral responses to the nephritogenic antigen were unaltered by deficiency of either GM-CSF or G-CSF, but glomerular T cell and macrophage numbers, as well as dermal delayed-type hypersensitivity to the nephritogenic antigen, were reduced in GM-CSF −/− mice. These studies demonstrate that endogenous GM-CSF plays a role in experimental glomerulonephritis in both the autologous and heterologous phases of injury.
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Brown, CB, P. Beaudry, TD Laing, S. Shoemaker, and K. Kaushansky. "In vitro characterization of the human recombinant soluble granulocyte- macrophage colony-stimulating factor receptor." Blood 85, no. 6 (March 15, 1995): 1488–95. http://dx.doi.org/10.1182/blood.v85.6.1488.bloodjournal8561488.
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We have cloned, expressed, and partially purified a naturally occurring, truncated, soluble form of the human granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor alpha subunit to investigate its biochemical and biologic properties. The soluble receptor species lacks the transmembrane and cytoplasmic domains that are presumably removed from the intact receptor cDNA by a mechanism of alternative splicing. The resulting soluble 55- to 60-kD glycosylated receptor species binds GM-CSF with a dissociation constant (kd) of 3.8 nmol/L. The soluble GM-CSF receptor successfully competes for GM-CSF binding not only with the transmembrane-anchored GM-CSF receptor alpha subunit but also with the native oligomeric high-affinity receptor complex. In addition, in human bone marrow colony-forming assays, the soluble GM-CSF receptor species can antagonize the activity of GM-CSF. Our data suggest that the soluble GM-CSF receptor may be capable of acting in vivo as a modulator of the biologic activity of GM-CSF.
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Ni, Keping, and Helen C. O'Neill. "Development of Dendritic Cells from GM-CSF-/-Miceinvitro: GM-CSF Enhances Production and Survival of Cells." Developmental Immunology 8, no. 2 (2001): 133–46. http://dx.doi.org/10.1155/2001/68024.
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The production of dendritic cells (DC) from haemopoietic progenitors maintained in long term stroma-dependent cultures (LTC) of spleen or bone marrow (BM) occurs independently of added granulocyte/macrophage colony stimulating factor (GM-CSF). The possibility that cultures depend on endogenous GM-CSF produced in low levels was tested by attempting to generate LTC from spleen and BM of GM-CSF-/-mice. Multiple cultures from GM-CSF-/-and wild type mice were established and compared for cell production. GM-CSF-/-LTC developed more slowly, but by 16 weeks produced cells resembling DC in numbers comparable to wild type cultures. LTC maintained distinct populations of small and large cells, the latter resembling DC. Cells collected from GM-CSF-/-LTC were capable antigen presenting cells (APC) for T cell stimulation and morphologically resembled DC. Large cells expressed the CD11b, CD11c, CD86, 33D1 and Dec-205 markers of DC. Addition of GM-CSF to GM-CSF-/-LTC increased the proportion of large, mature DC present in culture. Stromal cells from GM-CSF-/-LTC could support the differentiation of DC from early progenitors maintained in LTC without addition of GM-CSF. However, GM-CSF is not a critical factor in theinvitrogeneration of DC from progenitors. It can, however, substitute for stromal cells in increasing the survival of mature DC.
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Urashima, Mitsuyoshi, Gerrard Teoh, Dharminder Chauhan, Atsushi Ogata, Shuya Shirahama, Chiharu Kaihara, Masaharu Matsuzaki, et al. "MDM2 Protein Overexpression Inhibits Apoptosis of TF-1 Granulocyte-Macrophage Colony-Stimulating Factor–Dependent Acute Myeloblastic Leukemia Cells." Blood 92, no. 3 (August 1, 1998): 959–67. http://dx.doi.org/10.1182/blood.v92.3.959.414k21_959_967.
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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth factor for acute myeloblastic leukemia (AML) cells. Murine double minute 2 (MDM2) oncoprotein, a potent inhibitor of wild-type p53 (wtp53), can function both to induce cell proliferation and enhance cell survival, and is frequently overexpressed in leukemias. Therefore, we focused on the importance of MDM2 protein in GM-CSF–dependent versus GM-CSF– independent growth of AML cells. The TF-1 AML cell line, which has both wtp53 and mutant p53 genes, showed GM-CSF–dependent growth; deprivation of GM-CSF resulted in G1 growth arrest and apoptosis. MDM2 mRNA and protein were highly expressed in proliferating TF-1 cells in the presence of GM-CSF and decreased significantly with deprivation of GM-CSF. In contrast, p53 protein increased with GM-CSF deprivation. Ectopic overexpression of MDM2 in TF-1 AML cells conferred resistance to GM-CSF deprivation, and is associated with decreased p53 protein expression. Moreover, a variant of TF-1 cells that grows in a GM-CSF–independent fashion also expressed high levels of MDM2 and low levels of p53. These results suggest that GM-CSF–independent growth of AML cells is associated with overexpression of MDM2 protein and related modulation of p53 expression. © 1998 by The American Society of Hematology.
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Patel, Snehal, David McWilliams, Christine T. Fischette, Jaye Thompson, Mira Patel, and F. Joseph Daugherty. "Final five-year median follow-up safety data from a prospective, randomized, placebo-controlled, single-blinded, multicenter, phase IIb study evaluating the use of HER2/neu peptide GP2 + GM-CSF vs. GM-CSF alone after adjuvant trastuzumab in HER2-positive women with operable breast cancer." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 542. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.542.
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542 Background: The final analysis of the GP2 prospective, randomized, placebo-controlled, single-blinded, multicenter Phase IIb trial investigating GP2+GM-CSF administered in the adjuvant setting to node-positive and high-risk node-negative breast cancer patients with tumors expressing any degree of HER2 (immuno-histochemistry [IHC] 1-3+) ( NCT00524277) is now complete with 5 year follow-up. The trial enrolled HLA-A02 patients randomized to receive GP2+GM-CSF versus GM-CSF alone. It was previously reported that completion of the GP2+GM-CSF Primary Immunization Series (PIS) reduced recurrence rates to 0% over a 5 year follow-up period in HER2 3+ patients, who received a standard course of trastuzumab after surgery. Methods: Each enrolled and consented patient was randomly scheduled to receive a total of 6 GP2+GM-CSF (500 mcg GP2: 125 mcg GM-CSF) or GM-CSF only intradermal injections every 3-4 weeks as part of the PIS for the first 6 months and 4 GP2+GM-CSF or GM-CSF only booster intradermal injections every 6 months thereafter. Boosters were introduced during the trial, thus some patients did not receive all 4 boosters. Injection sight reactions were measured. Results: Safety data was analyzed to assess local and systemic toxicity of each treatment arm. Most subjects completed the planned PIS, 81 (91.0%) GP2+GM-CSF and 86 (94.5%) GM-CSF only. In addition, 77 GP2+GM-CSF and 80 GM-CSF only subjects received all 4 booster injections. The most common local toxicities were erythema, induration and pruritis and they occurred with similar frequency in the two treatment arms. Local reactions were reported by almost all subjects over the course of vaccinations. Occurring in a smaller percentage of subjects, the most common systemic toxicities were fatigue, headache, and myalgia/arthralgia, again with similar incidence by treatment group. The majority of all events reported were of Grade 1 mild severity (GP2+GM-CSF 92.5%, GM-CSF only 90.6%). Only 5 events in 4 subjects were considered Grade 3: induration and maculopapular rash/pruritis, in two GP2+GM-CSF subjects and chest pain and hypersensitivity reaction in two GM-CSF only subjects. The incidence of local reactions minimally increased with subsequent vaccinations however, the types of events remain unchanged. No serious adverse events were reported over the full 5 year treatment and follow-up periods. Conclusions: The study confirms the finding from the Phase I trial evaluating GP2+GM-CSF that the vaccine is safe and well-tolerated. The majority of patients experienced only mild local and systemic toxicities. Importantly, toxicities in the GP2+GM-CSF group were comparable to those seen in the GM-CSF only group, suggesting the toxicities are attributable to GM-CSF. Clinical trial information: NCT00524277.
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Kreitman, Robert J., and Ira Pastan. "Recombinant Toxins Containing Human Granulocyte-Macrophage Colony-Stimulating Factor and Either Pseudomonas Exotoxin or Diphtheria Toxin Kill Gastrointestinal Cancer and Leukemia Cells." Blood 90, no. 1 (July 1, 1997): 252–59. http://dx.doi.org/10.1182/blood.v90.1.252.
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Abstract The granulocyte-macrophage colony-stimulating factor receptor (GM-CSFR) is a potential target for toxin-directed therapy, because it is overexpressed on many leukemias and solid tumors and apparently not on stem cells. To investigate the potential therapeutic use of GM-CSF toxins, we fused human GM-CSF to truncated forms of either Pseudomonas exotoxin (PE) or diphtheria toxin (DT) and tested the cytotoxicity of the resulting GM-CSF–PE38KDEL and DT388–GM-CSF on human gastrointestinal (GI) carcinomas and leukemias. Toward gastric and colon cancer cell lines, GM-CSF–PE38KDEL was much more cytotoxic than DT388–GM-CSF, with IC50s (concentration resulting in 50% inhibition of protein synthesis) of 0.5 to 10 ng/mL compared with 4 to 400 ng/mL, respectively. In contrast, toward leukemia lines and fresh bone marrow cells DT388–GM-CSF was more cytotoxic than GM-CSF–PE38KDEL. The cytotoxicity of both GM-CSF–PE38KDEL and DT388–GM-CSF toward the human cells was specific, because it could be competed by an excess of GM-CSF. Binding studies indicated that human GM-CSF receptors were present on all of the human GI and leukemic cell lines tested, at levels of 540 to 3,700 sites per cell (kd = 0.2 to 2 nmol/L), and the number of sites per cell did not correlate with the cell type. A similar pattern of cytotoxicity was found with recombinant immunotoxins binding to the transferrin receptor, in that anti-TFR(Fv)–PE38KDEL was much more cytotoxic than DT388–anti-TFR(Fv) toward GI cells, but both were similar in their cytotoxic activity toward leukemia cells. The fact that PE is more effective than DT in killing GI but not leukemic tumor cells targeted by GM-CSF indicates a fundamental difference in the way PE or DT gains access to the cytosol in these cells. GM-CSF–PE38KDEL and DT388–GM-CSF deserve further evaluation as possible treatments for selected tumors.