Systematic review of toxicities of lineage-specific hematopoietic growth factors toxicities: Implications for biosimilar erythropoietins, thromopoietic receptor agonists, and continuous erythropoietin receptor agonists

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e20733-e20733
Author(s):  
A. Polish ◽  
A. T. Samaras ◽  
J. M. McKoy ◽  
D. P. West ◽  
S. M. Trifilio ◽  
...  
Keyword(s):  
Growth Factors ◽  
Erythropoietin Receptor ◽  
Hematopoietic Growth Factors ◽  
Thrombopoietin Receptor Agonists ◽  
Receptor Agonists ◽  
Gm Csf ◽  
Thrombopoietin Receptor ◽  
Delayed Recognition ◽  
Macrophage Colony ◽  
Meta Analyses

e20733 Background: Erythropoiesis stimulating agents (ESAs) and the granulocyte and granulocyte macrophage colony stimulating factors (G-CSF/GM-CSF) have been widely used for the past two decades. Recently, thrombopoietin receptor agonists, romiplostim and eltrombopag, biosimilar erythropoietins, and a continuous erythropoietin receptor agonist were licensed. Although lineage specific hematopoietic growth factors play important roles in the treatment of cancer and chronic kidney disease, recent basic and clinical research studies have identified toxicities. Herein, we compared toxicities of ESAs, thrombopoietins and G-CSF/CSFs and the implications of these findings. Methods: Meta-analyses, reviews, clinical guidelines, and FDA transcripts for G-CSF, GM-CSF, and ESAs were reviewed. For MGDF, romiplostim, and eltrombopag, clinical trial reports, reviews, and FDA transcripts were reviewed. The study period was 2000 to 2008. Results: See Table . Conclusions: Commonalities in toxicities exist across lineage specific hematopoietic growth factors. Delayed recognition of adverse effects with ESAs and G-CSF highlights the importance of anticipating toxicities with biosimilars and thrombopoietin receptor agonists. [Table: see text] No significant financial relationships to disclose.

Serious Adverse Drug Reactions (sADRS) Associated with Hematopoietic Growth Factors: A Systematic Review From the Southern Network on Adverse Reactions (SONAR) Program

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2555-2555 ◽  
Author(s):  
LeAnn Norris ◽  
Zaina Qureshi ◽  
Sara Barnato ◽  
Stephen Lai ◽  
Charles Bennett
Keyword(s):  
Growth Factors ◽  
Cancer Patients ◽  
Absolute Risk ◽  
Baseline Risk ◽  
Hematopoietic Growth Factors ◽  
Total N ◽  
Thrombopoietin Receptor Agonists ◽  
Receptor Agonists ◽  
Thrombopoietin Receptor ◽  
Cancer Setting

Abstract Abstract 2555 Erythrpoiesis stimulating agents (ESAs) and the granulocyte hematopoietic growth factors granulocyte colony stimulating factor (G-CSF) and pegylated G-CSF revolutionized supportive care approaches to anemia and neutropenia, respectively. Thrombopoietin-receptor agonists improve antibody-mediated thrombocytopenia management. For these drugs, as with all agents, a comprehensive understanding of sADRs is important, however, often difficult to do. We reviewed sADRS described in meta-analyses and web-site materials maintained by regulatory agencies and manufacturers reports (1989 to July 2010; n=2,094). Overall, 28 systematic reviews, six package inserts, three medication guides, four FDA Risk Evaluation and Mitigation Systems (REMS) materials, 16 Summaries of Product Characteristics/Product Assessment Reports were included. For ESAs, common sADRs associated with increased relative risks (RRs) included: mortality among cancer patients with chemotherapy-associated anemia or cancer patients not receiving active treatment (RRs: 1.1–1.2); cerebrovascular and cardiovascular events among chronic kidney disease patients ((RRs: 1.3, 1.9), and venous thromboembolism in the cancer setting (RRs;16-1.7). For G-CSF/pegylated-GCSF, rare instances of myelodysplasia/acute myeloid leukemia (MDS/AML) associated with statistically increased RRs were reported among breast cancer patients receiving chemotherapy in trials reported from one NCI-sponsored clinical trials group, one meta-analysis, and one review of Medicare/SEER databases (RR: 1.9–2.1), although the absolute risks were very small (< 2 per 100,000 treated patients). Other rarely reported sADRs (total N < 20) included splenic rupture following G-CSF stimulation of healthy peripheral blood stem donors. Bone marrow fibrosis and collagen deposition were reported with thrombopoietin receptor agonists, although the implications of this finding is uncertain. Also, instances of VTEs were reported among persons who developed high platelet counts following administration of these thrombopoeitin receptor agonists. SADRs are commonly associated with ESA administration in a range of settings, are uncommon occurrences with G-CSF/pegylated G-CSF, and are not well characterized for thrombopoieitin receptor agonists. Formal pharmacovigilance initiatives are ongoing, including FDA mandated REMS with restricted distribution requirement for ESAs in the cancer setting (APPRISE) and the NEXUS and the PROMACTA CARES programs for thrombopoeitin receptor agonists. ESAs (Cancer) ESAs (CKD) G-CSF/Pegylated G-CSF VTE Mortality Cerebrovascular and CVD AML/MDS RR 1.57 and 1.67 1.10 to 1.17 1.34 and 1.92 2.14 and 1.92 95% CI 1.31–1.87 and 1.35–2.06 1.02–1.20 and 1.06–1.30 1.03–1.74 and 1.38–2.26 1.12–4.08 and 1.19–3.07 Baseline Risk Absolute Risk Common Common Common Rare (2/100,000) Disclosures: Bennett: Pfizer: Consultancy.

scholarly journals Murine myeloid cells transformed by myb require fibroblast-derived or autocrine growth factors in addition to granulocyte-macrophage colony- stimulating factor for proliferation

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 209-216 ◽  
Author(s):  
EM Macmillan ◽  
TJ Gonda
Keyword(s):  
Growth Factors ◽  
Myeloid Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Autocrine Growth ◽  
Gm Csf ◽  
Absolute Dependence ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract Murine myeloid cells can be transformed in vitro by infection with recombinant retroviruses carrying activated myb genes. While these myb- transformed hematopoietic cells (MTHCs) can proliferate continuously in culture, they exhibit several characteristics of progenitor cells of the granulocyte-macrophage (GM) lineage, including an absolute dependence on hematopoietic growth factors (HGFs) such as GM colony- stimulating factor (GM-CSF) for survival and growth. Whereas we have previously shown that MTHCs respond synergistically to certain combinations of HGFs, we report here that MTHCs apparently require two HGFs for proliferation, because GM-CSF alone appears insufficient to promote growth when MTHCs are cultured at very low densities. However, proliferation can be stimulated by either increasing the density at which MTHCs are cultured (implying the production of an autocrine growth factor) or by the presence of a feeder layer of irradiated fibroblasts. We find that the activity of such feeder layers is greatest when the MTHCs are allowed to contact them directly; and by using mutant fibroblast lines, that it depends on the production of CSF- 1, but not Steel factor (SLF). In contrast, the autocrine factor appears not to be either CSF-1 or SLF, and the possibility is raised that it may represent a novel HGF activity. Potential implications of these results for normal and leukemic hematopoiesis are discussed.

scholarly journals Effects of granulocyte-macrophage colony-stimulating factor and erythropoietin on leukemic erythroid colony formation in human early erythroblastic leukemias

Blood ◽  
1987 ◽  
Vol 70 (4) ◽  
pp. 965-973 ◽  
Author(s):  
MT Mitjavila ◽  
JL Villeval ◽  
P Cramer ◽  
A Henri ◽  
J Gasson ◽  
...  
Keyword(s):  
Growth Factors ◽  
Plating Efficiency ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Erythroid Progenitors ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor ◽  
Autonomous Growth

Abstract Erythroid colonies from five patients with an early erythroblastic leukemia were obtained in “serum-free” cultures in the presence or absence of recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) and homogeneous native erythropoietin (Epo). Erythroid colonies with abnormal morphology and karyotype could be grown in different culture conditions. Their erythroid nature was ascertained by the presence of carbonic anhydrase I and glycophorin A. Leukemic erythroid progenitors strongly differed from normal progenitors in that spontaneous colonies were always obtained, sometimes with an extremely high plating efficiency (up to 5.7%). Colonies were found to be autonomous from exogenous hematopoietic growth factors because they were still obtained with a high plating efficiency at an average of one cell per culture in the absence of any added growth factor. No evidence for an autocrine secretion of Epo or GM-CSF emerged because Epo or GM- CSF could not be detected by biologic or radioimmunologic assays from the culture supernatant or cellular extracts of the leukemic cells and that Epo or GM-CSF antibodies did not block autonomous growth. In all cases, however, hematopoietic growth factors increased the plating efficiency of the abnormal erythroid progenitors. In the two “de novo” leukemias, leukemic erythroid progenitors responded primarily to Epo, whereas in the three other patients' (chronic myeloid leukemia) blast crisis they responded maximally to GM-CSF plus Epo. Recombinant erythroid-potentiating activity had no effect in any of these cases. These results suggest that the leukemic erythroid clonogenic cells arise from expansion of erythroid progenitors at different levels of differentiation (ie, CFU-E or BFU-E, depending upon the disease) and that autonomous growth is not related to a secretion of Epo or GM-CSF.

scholarly journals In vitro production of granulocyte-macrophage colony-stimulating factor in aplastic anemia: possible mechanisms of action of antithymocyte globulin

Blood ◽  
1991 ◽  
Vol 78 (1) ◽  
pp. 163-168 ◽  
Author(s):  
SD Nimer ◽  
DW Golde ◽  
K Kwan ◽  
K Lee ◽  
S Clark ◽  
...  
Keyword(s):  
Growth Factors ◽  
Aplastic Anemia ◽  
In Vitro Production ◽  
Hematopoietic Growth Factors ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Vitro Production ◽  
Normal Controls

Abstract Various abnormalities of lymphokine production have been described in patients with aplastic anemia. To determine if abnormal production of hematopoietic growth factors could contribute to the process of aplastic anemia we studied the in vitro production of human granulocyte- macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3) by phytohemagglutinin (PHA)- and antithymocyte globulin (ATG)- stimulated peripheral blood lymphocytes from 29 patients with aplastic anemia and 15 normal controls. GM-CSF production in response to 1% PHA was seen in nearly all samples (43 of 44) and similar amounts of GM-CSF were produced by patients with aplastic anemia and normal controls. Production of GM-CSF by ATG-stimulated lymphocytes was seen in 7 of 23 patients with aplastic anemia (30%); two of these patients also demonstrated low-level spontaneous production of GM-CSF. Production of GM-CSF in response to ATG was also seen in 2 of 11 normal controls (18%) and barely detectable spontaneous production of GM-CSF was seen in both. Biologically active IL-3 could also be detected in PHA- or ATG- stimulated peripheral blood mononuclear cells in several patients and normal controls. Our results indicate that lymphocytes from patients with aplastic anemia can be stimulated in vitro to produce normal quantities of GM-CSF, suggesting that impaired potential for production of T-cell derived hematopoietic growth factors is unlikely to account for the marrow hypoplasia seen. In several patients overproduction of GM-CSF was observed, consistent with the notion that some patients with aplastic anemia may have circulating activated T cells. We also demonstrate that ATG can stimulate the production of growth factors such as IL-3 and GM-CSF, supporting the role for ATG in stimulating hematopoiesis.

scholarly journals Activation of the Stress-Activated Protein Kinases by Multiple Hematopoietic Growth Factors With the Exception of Interleukin-4

Blood ◽  
1997 ◽  
Vol 89 (9) ◽  
pp. 3092-3096 ◽  
Author(s):  
Ian N. Foltz ◽  
John W. Schrader
Keyword(s):  
Growth Factors ◽  
Immune System ◽  
Protein Kinases ◽  
Activated Protein C ◽  
Interleukin 4 ◽  
Hematopoietic Growth Factors ◽  
Growth And Survival ◽  
Gm Csf ◽  
Macrophage Colony ◽  
And Function

Abstract The stress-activated protein/c-Jun N-terminal kinases (SAPK/JNK) have been shown to be activated by pro-inflammatory cytokines, as well as physical and chemical stresses. We now show that a variety of hematopoietic growth factors, including Steel locus factor (SLF ), granulocyte-macrophage colony-stimulating factor (GM-CSF ), and interleukin-3 (IL-3), all of which promote the growth and survival of various lineages of hematopoietic cells, activate the stress-activated protein kinases in the factor-dependent cell line MC/9. These hematopoietic growth factors activated both 46- and 55-kD isoforms of both SAPKγ and SAPKα. Furthermore, we demonstrate that SAPK activation correlated with the phosphorylation of SAPK/ERK kinase-1 (SEK1) after treatment with SLF or GM-CSF. Interestingly, IL-4, a cytokine with distinctive and important effects on the immune system, was the exception among the hematopoietic growth factors we examined in failing to induce activation of SAPKγ, SAPKα, or SEK1. These findings show that activation of SAPK is involved, not only in responses to stresses, but also in signaling by growth factors that regulate the normal development and function of cells of the immune system.

scholarly journals Murine myeloid cells transformed by myb require fibroblast-derived or autocrine growth factors in addition to granulocyte-macrophage colony- stimulating factor for proliferation

Blood ◽  
1994 ◽  
Vol 83 (1) ◽  
pp. 209-216 ◽  
Author(s):  
EM Macmillan ◽  
TJ Gonda
Keyword(s):  
Growth Factors ◽  
Myeloid Cells ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Autocrine Growth ◽  
Gm Csf ◽  
Absolute Dependence ◽  
Macrophage Colony ◽  
Stimulating Factor

Murine myeloid cells can be transformed in vitro by infection with recombinant retroviruses carrying activated myb genes. While these myb- transformed hematopoietic cells (MTHCs) can proliferate continuously in culture, they exhibit several characteristics of progenitor cells of the granulocyte-macrophage (GM) lineage, including an absolute dependence on hematopoietic growth factors (HGFs) such as GM colony- stimulating factor (GM-CSF) for survival and growth. Whereas we have previously shown that MTHCs respond synergistically to certain combinations of HGFs, we report here that MTHCs apparently require two HGFs for proliferation, because GM-CSF alone appears insufficient to promote growth when MTHCs are cultured at very low densities. However, proliferation can be stimulated by either increasing the density at which MTHCs are cultured (implying the production of an autocrine growth factor) or by the presence of a feeder layer of irradiated fibroblasts. We find that the activity of such feeder layers is greatest when the MTHCs are allowed to contact them directly; and by using mutant fibroblast lines, that it depends on the production of CSF- 1, but not Steel factor (SLF). In contrast, the autocrine factor appears not to be either CSF-1 or SLF, and the possibility is raised that it may represent a novel HGF activity. Potential implications of these results for normal and leukemic hematopoiesis are discussed.

scholarly journals Differentiation and functional activity of human eosinophilic cells from an eosinophil HL-60 subline: response to recombinant hematopoietic growth factors [published erratum appears in Blood 1992 Dec 1;80(11):2952]

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 788-794 ◽  
Author(s):  
I Fabian ◽  
M Lass ◽  
Y Kletter ◽  
DW Golde
Keyword(s):  
Cell Proliferation ◽  
Growth Factors ◽  
Functional Activity ◽  
Phorbol Esters ◽  
Enzyme Release ◽  
Hematopoietic Growth Factors ◽  
Phagocytic Capacity ◽  
Human Eosinophil ◽  
Gm Csf ◽  
Macrophage Colony

We studied the effect of hematopoietic growth factors (granulocyte- macrophage colony-stimulating factor [GM-CSF], granulocyte [G]-CSF, interleukin (IL)-1, IL-3, IL-5, IL-6, and macrophage [M]-CSF) on differentiation and functional activity of human eosinophilic HL-60 cells (Eos-HL-60) and compared them with effects on parental HL-60 promyelocytic leukemia cells. Purified biosynthetic GM-CSF and IL-5 enhanced cell proliferation and induced eosinophilic differentiation in the eosinophilic subline in both liquid and agar cultures. IL-3 and IL- 6 stimulated cell proliferation but had no effect on cell differentiation, whereas IL-1 and G-CSF affected neither differentiation nor proliferation of Eos-HL-60 cells under the conditions tested. GM-CSF-, IL-3-, and IL-5-treated Eos-HL-60 cells showed increased O2- production in response to phorbol esters (PMA), enhanced phagocytosis of Candida albicans, and release of the enzymes arylsulfatase, beta-glucuronidase and eosinophil peroxidase (EPO). The degranulation of eosinophils induced by GM-CSF, IL-5, and IL-3 may have relevance to the potential clinical toxicity of these hematopoietins, which also stimulate eosinophilopoiesis. G-CSF had no effect on enzyme release, oxidative metabolism, or phagocytic capacity of Eos-HL-60 cells. IL-5 did not affect proliferation, differentiation, or enzyme release in promyelocytic HL-60 cells. These results indicate the specificity of IL-5 for the eosinophil lineage, confirm the effects of GM-CSF and IL-3 on eosinophilopoiesis and mature eosinophil function in a model system, and indicate the absence of G-CSF and IL-1 stimulation of eosinophils. The Eos-HL-60 line is a useful model for studying human eosinophil responses to cytokines.

scholarly journals Rapid priming of human monocytes by human hematopoietic growth factors: granulocyte-macrophage colony-stimulating factor (CSF), macrophage-CSF, and interleukin-3 selectively enhance superoxide release triggered by receptor-mediated agonists

Blood ◽  
1992 ◽  
Vol 79 (6) ◽  
pp. 1553-1557 ◽  
Author(s):  
A Yuo ◽  
S Kitagawa ◽  
K Motoyoshi ◽  
E Azuma ◽  
M Saito ◽  
...  
Keyword(s):  
Growth Factors ◽  
Human Monocytes ◽  
Colony Stimulating Factor ◽  
Hematopoietic Growth Factors ◽  
Con A ◽  
Interleukin 3 ◽  
Gm Csf ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Stimulating Factor

Abstract The effects of hematopoietic growth factors on human monocyte superoxide (O2-) release were investigated by using purified human monocytes in suspension. Among growth factors studied, granulocyte- macrophage colony-stimulating factor (GM-CSF), macrophage-CSF (M-CSF), and interleukin-3 (IL-3) primed human monocytes and enhanced O2- release stimulated by the receptor-mediated agonists, N-formyl- methionyl-leucyl-phenylalanine (FMLP) and concanavalin A (Con A), but not by phorbol myristate acetate, which bypasses the receptors to stimulate the cells. The optimal priming was obtained by pretreatment of cells with 1 to 5 ng/mL (0.07 to 0.34 nmol/L) GM-CSF, 50 to 100 ng/mL (0.5 to 1.1 nmol/L) M-CSF, or 10 to 20 ng/mL (0.6 to 1.3 nmol/L) IL-3 for 10 minutes at 37 degrees C. Potency of the maximal priming effects on FMLP- or Con A-induced O2- release was GM-CSF greater than M- CSF = IL-3. The combination of the optimal concentrations of any two CSFs resulted in the effect of more potent priming agent alone. Enhancement of O2- release by GM-CSF was observed over the complete range of effective concentrations of FMLP (10(-8) to 10(-6) mol/L). The pretreatment of monocytes with granulocyte-CSF (50 ng/mL), interferon- gamma (1,000 U/mL), or IL-4 (20 ng/mL) for 10 minutes at 37 degrees C had no effect on O2- release stimulated by FMLP or Con A. These findings show that GM-CSF, M-CSF, and IL-3 selectively enhance O2- release in human monocytes triggered by receptor-mediated agonists after short-term preincubation.

scholarly journals Differentiation and functional activity of human eosinophilic cells from an eosinophil HL-60 subline: response to recombinant hematopoietic growth factors [published erratum appears in Blood 1992 Dec 1;80(11):2952]

Blood ◽  
1992 ◽  
Vol 80 (3) ◽  
pp. 788-794 ◽  
Author(s):  
I Fabian ◽  
M Lass ◽  
Y Kletter ◽  
DW Golde
Keyword(s):  
Cell Proliferation ◽  
Growth Factors ◽  
Functional Activity ◽  
Phorbol Esters ◽  
Enzyme Release ◽  
Hematopoietic Growth Factors ◽  
Phagocytic Capacity ◽  
Human Eosinophil ◽  
Gm Csf ◽  
Macrophage Colony

Abstract We studied the effect of hematopoietic growth factors (granulocyte- macrophage colony-stimulating factor [GM-CSF], granulocyte [G]-CSF, interleukin (IL)-1, IL-3, IL-5, IL-6, and macrophage [M]-CSF) on differentiation and functional activity of human eosinophilic HL-60 cells (Eos-HL-60) and compared them with effects on parental HL-60 promyelocytic leukemia cells. Purified biosynthetic GM-CSF and IL-5 enhanced cell proliferation and induced eosinophilic differentiation in the eosinophilic subline in both liquid and agar cultures. IL-3 and IL- 6 stimulated cell proliferation but had no effect on cell differentiation, whereas IL-1 and G-CSF affected neither differentiation nor proliferation of Eos-HL-60 cells under the conditions tested. GM-CSF-, IL-3-, and IL-5-treated Eos-HL-60 cells showed increased O2- production in response to phorbol esters (PMA), enhanced phagocytosis of Candida albicans, and release of the enzymes arylsulfatase, beta-glucuronidase and eosinophil peroxidase (EPO). The degranulation of eosinophils induced by GM-CSF, IL-5, and IL-3 may have relevance to the potential clinical toxicity of these hematopoietins, which also stimulate eosinophilopoiesis. G-CSF had no effect on enzyme release, oxidative metabolism, or phagocytic capacity of Eos-HL-60 cells. IL-5 did not affect proliferation, differentiation, or enzyme release in promyelocytic HL-60 cells. These results indicate the specificity of IL-5 for the eosinophil lineage, confirm the effects of GM-CSF and IL-3 on eosinophilopoiesis and mature eosinophil function in a model system, and indicate the absence of G-CSF and IL-1 stimulation of eosinophils. The Eos-HL-60 line is a useful model for studying human eosinophil responses to cytokines.

scholarly journals Interferon-gamma stimulates the survival and influences the development of bipotential granulocyte-macrophage colony-forming cells

Blood ◽  
1991 ◽  
Vol 78 (10) ◽  
pp. 2588-2594 ◽  
Author(s):  
O Kan ◽  
CM Heyworth ◽  
TM Dexter ◽  
PJ Maudsley ◽  
N Cook ◽  
...  
Keyword(s):  
Growth Factors ◽  
Dna Synthesis ◽  
Interferon Gamma ◽  
Direct Interaction ◽  
Soft Agar ◽  
Hematopoietic Growth Factors ◽  
Ifn Gamma ◽  
Gm Csf ◽  
Sodium Hydrogen ◽  
Macrophage Colony

Abstract The effects of interferon-gamma (IFN-gamma) on a highly enriched population of granulocyte-macrophage colony-forming cells (GM-CFC) were assessed. When added with myeloid growth factors (interleukin-3 [IL-3], granulocyte-macrophage colony-stimulating factor [GM-CSF], or macrophage-CSF [M-CSF]), IFN-gamma inhibited the formation of colonies in soft agar assays. Furthermore IFN-gamma stimulated an increase in the number of macrophages present in colonies formed in the presence of IL-3. IFN-gamma also inhibited M-CSF-, GM-CSF-, or IL-3-stimulated [3H]- thymidine incorporation in highly enriched GM-CFC. However, when added in the absence of hematopoietic growth factors, IFN-gamma promoted the survival of GM-CFC and had a modest stimulatory effect on DNA synthesis. The direct interaction of the IFN with GM-CFC was confirmed by showing its ability to rapidly activate the sodium/hydrogen antiport in GM-CFC, as do the mitogens GM-CSF, M-CSF, and IL-3. However, the effect of IFN-gamma on intracellular pH and DNA synthesis was transient and pretreatment with IFN markedly inhibited the ability of GM-CSF, M- CSF, and IL-3 to activate the sodium/hydrogen antiport. IFN-gamma has a dual effect on GM-CFC, decreasing the rate of cell death but also limiting the proliferative response to CSFs.

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