Role Of Granulocyte-macrophage Colony-stimulating Factor Research Articles

Questions about the role of granulocyte-macrophage colony-stimulating factor as adjunct to non-Hodgkin's lymphoma chemotherapy [letter; comment

Questions about the role of granulocyte-macrophage colony-stimulating factor as adjunct to non-Hodgkin's lymphoma chemotherapy [letter; comment

Leukotriene B4 generation and DNA fragmentation induced by leukocidin from Staphylococcus aureus: protective role of granulocyte-macrophage colony-stimulating factor (GM-CSF) and G-CSF for human neutrophils.

We studied the effect of leukocidin from Staphylococcus aureus V8 strains (Luk-PV) on the generation of Leukotriene B4 (LTB4) and its metabolites from human polymorphonuclear neutrophils (PMNs). Significant amounts of LTB4 were generated by PMNs after leukocidin exposure in a time- and dose-dependent manner, as shown by reversed-phase high-performance liquid chromatography analysis. In this regard, the S and F components of leukocidin acted synergistically. The calcium ionophore A23187 induced LTB4 generation, and the metabolism of exogenously added LTB4 into biologically less active omega-oxidated compounds was significantly decreased after leukocidin exposure. Priming of PMNs with granulocyte-macrophage colony-stimulating factor (GM-CSF) or G-CSF prior to leukocidin exposure substantially increased toxin- and calcium ionophore A23187-induced LTB4 formation. The inhibitory effects of leukocidin on mediator release were accompanied by membrane damage and DNA fragmentation, which were both restored after pretreatment with GM-CSF. The data suggest that the presence of costimulatory priming factors such as GM-CSF or G-CSF in the microenvironment of an inflammatory focus determines the pathophysiological effects induced by S. aureus leukocidin.

Prediction of the role of granulocyte-macrophage colony-stimulating factor in animals and man from in vitro results.

The possibility of predicting the clinical effects of cytokines from in vitro data is discussed, using GM-CSF as an example. GM-CSF incubated with bone marrow cells has been shown to induce proliferation and colony formation, predominantly of the colony-forming unit granulocyte and granulocyte-macrophage types. Daily treatment of normal monkeys with GM-CSF resulted in transient neutropenia followed by neutrophilia. After withdrawal of GM-CSF the neutrophil levels returned to baseline. Predictably, GM-CSF administration results in accelerated neutrophil recovery in patients with chemotherapy-induced neutropenia. GM-CSF has also been shown to induce microbial killing by neutrophils and monocytes in vitro. This activity translated into a dose-related protection of GM-CSF-pretreated mice infected with lethal doses of micro-organisms. Interleukin-3 (IL-3) increases the cellularity of the bone marrow and GM-CSF can induce mobilization of bone marrow cells into the peripheral blood. Therefore, it was predicted and subsequently proved that a combination of these cytokines is synergistic, increasing the yields of peripheral blood progenitor cells which could be collected and then retransplanted into patients undergoing myeloablative chemotherapy. Monkeys injected with recombinant human IL-3 and GM-CSF had increased antibody titres to human IL-3 compared with monkeys given IL-3 alone, suggesting a potential use of GM-CSF which was not predicted from its in vitro results, that of vaccine adjuvancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Potential role of granulocyte-macrophage colony-stimulating factor as vaccine adjuvant.

The uses of GM-CSF as an immunomodulator and vaccine adjuvant are reviewed. GM-CSF has a variety of effects on immune responses: it induces class II major histocompatibility complex antigen expression on the surface of macrophages; it enhances dendritic cell maturation and migration; it results in a localized inflammation at the injection site; and it has marked effects on maturation of haematopoietic progenitor cells in the bone marrow. Animal and human studies suggest that administration of GM-CSF can increase antibody titres to foreign antigens. Monkeys injected with human interleukin (IL)-3 plus GM-CSF, at a different injection site, developed peak antibody titres which were 8- to 30-fold higher than those in monkeys injected with IL-3 alone. In a study of ovarian cancer patients receiving GM-CSF to prevent chemotherapy-induced neutropenia, two patients who had demonstrated a low titre of antithyroid antibodies prior to the study showed an increase in antibody titre and transient thyroiditis after administration of GM-CSF. Recently a GM-CSF/antigen fusion protein has been tested. An antibody corresponding to a specific idiotype expressed on B-cell lymphomas was fused to GM-CSF and injected into mice with B-cell lymphoma xenografts. The mice developed antibodies to the lymphoma and there was a protective effect against disease progression. Preliminary results of clinical trials using GM-CSF in humans suggest that it enhances antibody responses to hepatitis B vaccine. On the basis of these preliminary results, several clinical trials are being planned and it would appear that GM-CSF has potential as a vaccine adjuvant.

Role of granulocyte-macrophage colony-stimulating factor as adjuvant therapy for fungal infection in patients with cancer.

A pilot study was conducted to evaluate the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) as adjuvant therapy for fungal infections in patients with cancer. GM-CSF was added to amphotericin B in the treatment of cancer patients with proven major-organ or disseminated fungal infection. The dose of GM-CSF ranged from 100 to 750 micrograms/(m2.d). Of eight evaluable patients, six had a neutrophil response to GM-CSF. Four of these patients were completely cured of the fungal infection, and two had a partial response. However, a capillary-leak syndrome developed in three patients, an adverse effect suggesting that the dose of GM-CSF was excessive.

A novel role for GM-CSF: enhancement of pregnancy specific interferon production, ovine trophoblast protein-1

Transient and massive production of ovine trophoblast protein-1 (oTP-1) by preimplantation conceptuses seems to be a critical event required for the establishment of successful pregnancy. We have previously demonstrated that one of several oTP-1 genes is predominantly expressed between days 13 and 20 of pregnancy and that this oTP-1 gene contains an AP-1 site, a transcription enhancer element, in the 5'-flanking region. We have obtained evidence, indicating a linkage between cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and conceptus production of the trophoblast interferon (IFN), oTP-1. These are: 1) oTP-1 production (both polypeptide and mRNA) is enhanced by the addition of GM-CSF in vitro and 2) GM-CSF mRNA is localized in the luminal and glandular epithelium of the uterine endometrium. Based on these observations, we propose that the massive amounts of oTP-1 produced during the period of pregnancy establishment is stimulated at least in part by maternal GM-CSF.

A novel role for GM-CSF: enhancement of pregnancy specific interferon production, ovine trophoblast protein-1.

Transient and massive production of ovine trophoblast protein-1 (oTP-1) by preimplantation conceptuses seems to be a critical event required for the establishment of successful pregnancy. We have previously demonstrated that one of several oTP-1 genes is predominantly expressed between days 13 and 20 of pregnancy and that this oTP-1 gene contains an AP-1 site, a transcription enhancer element, in the 5'-flanking region. We have obtained evidence, indicating a linkage between cytokine granulocyte macrophage-colony stimulating factor (GM-CSF) and conceptus production of the trophoblast interferon (IFN), oTP-1. These are: 1) oTP-1 production (both polypeptide and mRNA) is enhanced by the addition of GM-CSF in vitro and 2) GM-CSF mRNA is localized in the luminal and glandular epithelium of the uterine endometrium. Based on these observations, we propose that the massive amounts of oTP-1 produced during the period of pregnancy establishment is stimulated at least in part by maternal GM-CSF.

The role of GM-CSF in lung cancer: a review of the literature

The first hematopoietic growth factor, erythropoietin was discovered by Carnot and Deflandre in the early 1900’s when they showed that plasma from anemic animals would induce erythrocytosis in normal rabbits [l]. It was not until 60 years later that growth factors for myeloid and monocytic cells were described. The discovery of these hematopoietic growth factors was made possible by the development of semi-solid media to grow colonies of normal human bone marrow. Bradley and Metcalf [2] described methods for growing murine hematopoietic progenitor cells, and Robinson and Pike [3] refined these techniques and described methods for growing human progenitor cells in vitro. They subsequently showed that plasma from infected patients and supernatants from human cells infected with bacteria would increase the number of these bone marrow colonies and were thus termed colony stimulating factors or CSFs [4]. Much of the early work was conducted at the Walter and Eliza Hall Institute in Melbourne. Fig. 1 shows a photograph of some of the important scientists in the group at the time. The development of clinical application of the colony stimulating factors awaited the purification of the individual proteins, the cloning of their genes and the expression of these genes in bacterial and yeast cells to mass produce the factors [5,6]. At present, there are over 19 distinct factors which stimulate the growth of various cell lineages within the marrow. This paper will focus on studies of granulocyte macrophage colony stimulating factor (GM-CSF) in human lung cancer. Some studies evaluating other myeloid and monocyte growth factors such as granulocyte colony stimulating factor (GCSF), macrophage colony stimulating factor (M-CSF) and multi-CSF (IL-3) and some studies evaluating GM-CSF in other conditions will also be discussed briefly.

Role of granulocyte-macrophage colony-stimulating factor in pulmonary fibrosis induced in mice by bleomycin.

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in pulmonary fibrosis elicited in mice by the intratracheal instillation of bleomycin was investigated by (1) evaluation of GM-CSF mRNA levels, (2) administration of GM-CSF, and (3) administration of anti-GM-CSF antibody. A significant increase of the GM-CSF mRNA level was evident in the lung RNA on day 5 after bleomycin instillation, but not on day 15. Abdominal infusion of GM-CSF (0.5 micrograms/h during days 7-15) did prevent the collagen deposition induced by bleomycin, as measured by the lung hydroxyproline content on day 15. In contrast, anti-GM-CSF antibody markedly aggravated the collagen deposition. On histological sections the proportion of lungs showing fibrosing alveolitis was decreased by GM-CSF and increased by anti-GM-CSF IgG. The percentage and number of macrophages within the bronchoalveolar lavage (BAL) fluid was increased by GM-CSF infusion and decreased by anti-GM-CSF antibodies. This study demonstrates that pulmonary GM-CSF has an inhibitory influence upon the alveolar remodeling and collagen deposition associated with pulmonary fibrosis.

Effect of butyric acid on induction of differentiation into eosinophil-like cells in human eosinophilic leukemia cells, EoL-1 cell line: possible role of granulocyte-macrophage colony-stimulating factor as an autocrine differentiating factor.

EoL-1 cells differentiated into mature eosinophil-like cells when incubated with butyric acid (BA). The differentiated cells possessed many granules that stained with Luxol fast blue and acquired the ability to produce leukotriene C4 and eosinophil cationic protein (ECP), and migrated toward some eosinophillotactic attractants, including PAF, IL-5, IL-3 and GM-CSF. Monoclonal antibody to GM-CSF and IL-5, especially GM-CSF, strongly decreased the ability of BA to induce differentiation, whereas antibody to IL-3 did not. Recombinant human (rh) IL-3, rhGM-CSF and recombinant mouse (rm) IL-5, by themselves, did not have the ability to induce differentiation. On the other hand, the presence of these cytokines significantly (p < 0.01) augmented BA-induced cell differentiation. Other cytokines including rhIL-1 alpha/beta, rhIL-2, rhIL-4, rhIL-6, rhIL-8, rhTNF-alpha and rhIFN-gamma had no effect on differentiation. Expression of GM-CSF and GM-CSF receptor mRNA was detected in cellular RNA obtained from BA-stimulated EoL-1 cells. Moreover, about 5-10 pg/ml of GM-CSF was detected in the culture supernatant of BA-stimulated EoL-1 cells. These findings suggested that BA-induced EoL-1 cell differentiation was elicited under the influence of GM-CSF endogenously produced in these cells. GM-CSF also seemed to be an autocrine differentiating factor in EoL-1 cells.

The Role of GM-CSF, G-CSF, Interleukin-3, and Erythropoietin in Myelodysplastic Syndromes

Hematopoietic growth factors are being used in patients with myelodysplastic syndromes with increasing frequency to reverse pancytopenia. Treatment with granulocyte-macrophage colony stimulating factor (GM-CSF) and granulocyte colony stimulating factor (G-CSF) has resulted in an increase in segmented neutrophil counts and a reduction in the infection rate, whereas a stimulatory effect on platelet count and hematocrit was uncommon. Progression to acute leukemia has been observed, but could have been due to the natural course of the disease. Combination therapy with GM-CSF and low-dose cytosine-arabinoside is being studied in clinical trials. Early results with interleukin-3 have demonstrated a stimulatory effect on neutrophil counts as well as on platelet counts. High doses of erythropoietin have only been successful in 10% of treated patients to improve erythropoiesis.

Granulocyte-Macrophage Colony-Stimulating Factor Synergizes With Interleukin-6 in Supporting the Proliferation of Human Myeloma Cells

AbstractThe role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo, recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P <.01). Furthermore, GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact, this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line), rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL-6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells, nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients, it is possible that GM-CSF, produced locally by the tumoral environment, enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.

Granulocyte-macrophage colony-stimulating factor synergizes with interleukin-6 in supporting the proliferation of human myeloma cells [see comments

The role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in the growth of multiple myeloma (MM) was investigated in 21 patients with MM. In 17 patients with proliferating myeloma cells in vivo, recombinant GM-CSF significantly increased the endogenous-IL-6-mediated spontaneous myeloma cell proliferation occurring in 5-day cultures of tumor cells in vitro (P less than .01). Furthermore, GM-CSF was detected in 5-day culture supernatants of myeloma bone marrow cells. This endogenous GM-CSF was produced by the myeloma bone marrow microenvironment but not by myeloma cells and contributed to the spontaneous myeloma-cell proliferation observed in 5-day cultures. In fact, this proliferation was partially blocked (67%) by anti-GM-CSF monoclonal antibodies. The stimulatory effect of rGM-CSF was mediated through IL-6 because it was abrogated by anti-IL-6 monoclonal antibodies. rGM-CSF did not reproducibly increase the endogenous IL-6 production in short-term cultures of bone marrow cells of MM patients. Using an IL-6-dependent myeloma cell line (XG-1 cell line), rGM-CSF was shown to act directly on myeloma cells stimulating by twofold their IL- 6 responsiveness. rGM-CSF did not induce any IL-6 production in XG-1 cells, nor was it able to sustain their growth alone. Although no detectable GM-CSF levels were found in the peripheral or bone marrow blood of MM patients, it is possible that GM-CSF, produced locally by the tumoral environment, enhances the IL-6 responsiveness of myeloma cells in vivo in a way similar to that reported here in vitro.

Inducible Production of Interleukin-6 by Human Polymorphonuclear Neutrophils: Role of Granulocyte-Macrophage Colony-Stimulating Factor and Tumor Necrosis Factor-alpha

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli-derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.

Inducible production of interleukin-6 by human polymorphonuclear neutrophils: role of granulocyte-macrophage colony-stimulating factor and tumor necrosis factor-alpha

The recent demonstration of the ability of human polymorphonuclear neutrophils (PMN) to secrete various cytokines in response to the granulocyte activator granulocyte-macrophage colony-stimulating factor (GM-CSF) but not to other cytokines, has led to the identification of PMN as biosynthetically active cells. In this study we have investigated the ability of PMN to secrete interleukin-6 (IL-6), a molecule known to be involved in inflammatory reactions. Using RNA blotting analysis and bioassays, we show that PMN could be induced to synthesize transcripts specific for IL-6, indistinguishable in size from IL-6 mRNA produced by activated human macrophages. Consequently, PMN released IL-6-like activity into their culture supernatants that could be neutralized by monospecific anti-IL-6 antibody. Interleukin-6 secretion by PMN, however, required previous stimulation with GM-CSF or tumor necrosis factor-alpha (TNF-alpha), whereas other cytokines, including interleukin-3 (IL-3), granulocyte-CSF (G-CSF), macrophage-CSF (M-CSF), interferon gamma (IFN-gamma), and lymphotoxin (LT), failed to induce IL-6 mRNA accumulation and protein secretion by PMN. Similar to GM-CSF and TNF-alpha, other compounds, including the inhibitor of protein synthesis cyclohexemide (CHX), endotoxin (Escherichia coli- derived lipopolysaccharide), and phorbol myristate acetate (PMA) (but not the chemoattractant N-formyl-methionyl-leucyl-phenylalanine [FMLP]), induced detectable levels of IL-6 transcripts in PMN.

GM-CSF: A regulatory molecule for NK activity in the bone marrow

Abstract : The regulation of myeloid proliferation, differentiation and activation by granulocyte macrophage colony stimulating factor (GM-CSF) has been recognized. However, the role of GM-CSF in NK proliferation and activation is unclear even through NK cells have been shown to synthesize and secrete GM-CSF. The activation of peripheral blood NK cells and their development from precursors in the bone marrow (BM) are suggested to be regulated by multiple factors. We have shown that in vivo administration of GM-CSF to normal monkeys resulted in a latent enhancement of peripheral blood NK activity, with no measurable change during the administration period. These suggested that GM-CSF treatment had an effect on NK cell development in the BM. To evaluate this possibility, we characterized the NK cell populations in the BM of normal primates during and after GM-CSF treatment. Reprints.

Clinical Role of Granulocyte-Macrophage Colony-Stimulating Factor

The activity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) for increasing leukocyte production and enhancing mature neutrophil function has been clearly demonstrated in phase I clinical trials in patients with a variety of hematologic and malignant diseases. The focus of current studies includes determination of optimal administration schedules and its use in combination with myelosuppressive chemotherapy, radiation therapy or antimicrobial agents. The utility of GM-CSF as a stimulant of host defense against infections and tumors is also under study.

The role of granulocyte-macrophage colony-stimulating factor in the pathogenesis of experimental murine leishmaniasis.

The role of granulocyte-macrophage colony-stimulating factor in the pathogenesis of experimental murine leishmaniasis.