GM-CSF

In addition to stimulating the production of mature neutrophils during haematopoiesis, G-CSF also affects the function of mature neutrophils. These effects are discussed in 7.2.1. 

Recombinant GM-CSF (produced in Escherichia coli, yeast or COS cells) has been tested for its ability to affect haematopoiesis in primates and humans. Because of its relatively short half-life in the circulation, daily administration (usually via intravenous infusion) is required. Administration results in a transient neutropenia, monocytopenia and eosinopenia within 30 min of administration, presumably because of the ability of GM-CSF to stimulate the expression of adhesins and hence increase the numbers of leukocytes adhered to the capillary endothelium in the marginated pool. Additionally, these leukocytes may accumulate in the lungs after GM-CSF administration, which may contribute to the decrease in the observed numbers 

In addition to its effects on haematopoietic cells, GM-CSF can also affect the function of mature cells. GM-CSF treatment increases the survival, cytotoxicity and eicosanoid formation by eosinophils, and can increase the tu-mouricidal activity, cytokine expression, surface antigen expression and oxidative metabolism of macrophages. It is chemotactic for endothelial cells, can induce the proliferation of some tumour cells, stimulates histamine release from basophils and affects the viability and function of Langerhans cells. Its effects on mature neutrophils are described in 7.2.1, 7.3.4. 

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Glucocorticoids have been shown to inhibit gene transcription of other proteins involved in the inflammatory process, including the key inflammation mediators called cytokines (IL-1, IL3—6, IL8, GM-CSF, TNFa) (10,58,63—65). Steroids have been also shown to suppress the formation of cytokine receptors (10) dexamethasone, in particular, downregulates gene transcription of angiotensin II type 2 receptors (66). 

GM-CSF, G-CSF, M-CSF, multi-CSF cytotoxic injury bone marrow transplantation myelodysplastic syndromes AIDS neutropenia rodent and human... 

Similar results have been reported in sublethaHy and lethaHy irradiated dogs, where G-CSF reduced the severity and duration of neutropenia and the duration of thrombocytopenia (161). G-CSF increases the survival of lethaHy irradiated animals by inducing eadier recovery of neutrophils and platelets. GM-CSF also decreases the severity and duration of neutropenia in dogs exposed to 2.4 Gy (2400 rad) TBI, but does not influence monocyte or lymphocyte recovery (162), indicating its expected selective action. 

Clinically, GM-CSF or G-CSF have been used to accelerate recovery after chemotherapy and total body or extended field irradiation, situations that cause neutropenia and decreased platelets, and possibly lead to fatal septic infection or diffuse hemorrhage, respectively. G-CSF and GM-CSF reproducibly decrease the period of granulocytopenia, the number of infectious episodes, and the length of hospitalization in such patients (152), although it is not clear that dose escalation of the cytotoxic agent and increased cure rate can be rehably achieved. One aspect of the effects of G-CSF and GM-CSF is that these agents can activate mature cells to function more efficiently. This may, however, also lead to the production of cytokines, such as TNF- a, that have some toxic side effects. In general, both cytokines are reasonably well tolerated. The side effect profile of G-CSF is more favorable than that of GM-CSF. Medullary bone pain is the only common toxicity. 

The role of cytokine therapy in the management of radiation accident victims has been summarized (152). In GoiBnia in Brazil in 1987, eight radiation accident victims were treated with GM-CSF one month after radiation exposure. Marked increases in granulocyte production were induced in five persons, although this did not prevent death. 

Interleukin-1 OC and (3. IL-1 has radioprotective activity toward BM and other tissues (151,164). IL-1 is produced in response to endotoxin, other cytokines, and microbial and viral agents, primarily by monocytes and macrophages. Other nucleated cells can also produce it. IL-1 appears to play an important role in the regulation of normal hemopoiesis directly by stimulating the most primitive stem cells and indirectly by stimulating other hemopoietic factors, including G-CSF, GM-CSF, M-CSF, and IL-6. 

A critical step in radioprotection involves the IL-1 receptors. Monoclonal antibodies to the type 1 IL-1 receptor block IL-l-induced radioprotection (167). Although this receptor is not present on BM cells, it is present on fibroblasts, which suggests that the effects of IL-1 on stem cells maybe largely indirect and mediated by stromal cell activation (168). Anti-IL-1 receptor (type 1) also sensitizes normal mice to the effects of TBI, which suggests that endogenous IL-1 has an intrinsic radioprotective role. IL-6 induction by IL-1, but not CSF levels, is inhibited, which supports the concept that G-CSF and GM-CSF are insufficient by themselves at radioprotecting stem cells and indicates a contributory role for IL-6. Anti-IL-6 antibody blocks IL-1 and TNF-induced radioprotection and also decreases the intrinsic radioresistance of mice, as does anti-TNF- a (169). 

Anti-SCF antibody similarly abrogates Hpopolysaccharide- and IL-l-induced radioprotection (170) and sensitized mice to radiation. Such effects are not obtained using anti-IL-3, anti-IL-4, or anti-GM-CSF antibodies. SCF, IL-1, IL-6, and TNF- a have acknowledged interactive roles in the normal... 

Basic FGF can also stimulate murine hemopoietic progenitors in vitro. It is synergistic with hemopoietic growth factors such as GM-CSF, EPO, and Meg-CSF and has radioprotective activity in vivo, increasing the number of day-9 and day-12 CFU-S from lethaUy irradiated animals (195). Furthermore, b-FGF combiaed with GM-CSF protects against the killing of murine and human CFU-GM exposed to radiation in vitro (195). 

G-CSF (recombinant products molgramostim, sar-gramostim) is locally active and remains at the site of infection to localize and activate neutrophils [4]. Like G-CSF, GM-CSF stimulates the proliferation,... 

SCF (recombinant product ancestim) is an early-acting hematopoietic growth factor that stimulates the proliferation of primitive hematopoietic and nonhema-topoietic cells [7]. In vitro, SCF has minimal effect on hematopoietic and nonhematopoietic progenitor cells, but it synergistically increases the activity of other hematopoietic growth factors, such as G-CSF, GM-CSF, and EPO. SCF stimulates the generation of dendritic cells in vitro and mast cells in vivo. 

Neutropenia is a drop in the number of circulating leukocytes, especially neutrophils. It can be induced by a variety of drugs. Treatment with cytotoxic antineo-plastic drags usually results in severe neutropenia, which can be treated with colony-stimulating factors (G-CSF, GM-CSF). 

G-protein-coupled Receptor Kinases (GRKs) G-protein-coupled Receptors G-proteins and Wnt Signaling Granulocyte-CSF (G-CSF) Granulocyte-macrophage-CSF (GM-CSF)... 

Rheumatoid synovial cells produce a broad range of cytokines (Brennan et al., 1991). The formation of IL-la, IL-1 /3, GM-CSF, G-CSF, TNFa and other cytokines may be under the direct influence of ox-LDL and/or... 

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