Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04141 (granulocyte-macrophage colony-stimulating factor)
 6,790 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large body of clinical experience on the adverse consequences of cytokine administration has accumulated since the last decade. Side-effects reported after the therapeutic use of cytokines has provided evidence that activation of the immune response may sometimes have deleterious consequences. Several effects appeared as a direct consequence of the immune activation induced by cytokines, e.g. flu-like reactions, vascular leak syndrome. Cytokine-induced exacerbation of underlying diseases or immune dysregulation were other complications of growing concern. Interferon-alpha (IFN-alpha) treatment has now been clearly linked with the exacerbation or the occurrence of several types of autoantibodies or autoimmune diseases (thyroiditis, systemic lupus erythematosus, hematologic disorders, insulin-dependent diabetes mellitus) or diseases involving altered cell-mediated immune functions (inflammatory dermatologic diseases, nephritis, pneumonitis, colitis). By contrast immunological side-effects of IFN-beta and IFN-gamma have been seldom reported. However, the extent of clinical experience with both of these cytokines is still very limited. Interleukin-2 (IL-2) has also been implicated in various conditions that may involve immunopathological processes (thyroid disorders, rheumatoid arthritis, dermatological diseases, interstitial nephritis). Growth factors have been more specifically linked with the development or the exacerbation of dermatological inflammatory diseases through neutrophils, monocytes/macrophages or eosinophils activation (e.g. cutaneous vasculitis and generalized cutaneous eruption, Sweet's syndrome, bullous eruption, psoriasis). Exacerbation of autoimmune thyroiditis was described with granulocyte-macrophage colony-stimulating factor (GM-CSF) only. The immunogenicity of cytokines is also of great relevance and the occurrence of antibodies binding IFN-alpha and IFN-beta, IL2 and GM-CSF have been reported. While the clinical significance of non-neutralizing antibodies is not clearly established, an absence of response or reversal of clinical efficacy has been described in patients developing neutralizing antibodies. Finally, several isolated reports have recently suggested that IFN-alpha treatment may be associated with several immunosuppressive effects while IL-2 is clinically associated with an increased incidence of infectious complications.
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PMID:Immune-mediated side-effects of cytokines in humans. 863 83

A number of cytokines are used as haemopoietic growth factors and this review focuses on toxicities associated with granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-1, IL-3, IL-4, IL-6 and macrophage colony-stimulating factor (M-CSF). Both GM-CSF and G-CSF, currently approved for clinical use, are generally well tolerated by the majority of patients during short term administration. Constitutional symptoms and bone pain are the most frequently reported adverse effects, but they are rarely treatment-limiting. Reactivation of rheumatoid symptoms, and exacerbation of autoimmune thyroiditis or autoimmune haematological disorders have sometimes been described. Severe cardiovascular complications include the possibility for arterial thromboses and the vascular leak syndrome, which is more specifically observed with GM-CSF. Reports of several cases and small series of patients have suggested that growth factors might increase the pulmonary toxicity of chemotherapy, a possibility that remains debated and requires further attention. Generalised or local cutaneous reactions are frequently noted with GM-CSF. Leukocytoclastic vasculitis was observed with both growth factors, while neutrophilic dermatoses have been mostly described with G-CSF. Exacerbation of psoriasis and isolated anaphylactic reactions have appeared with GM-CSF and G-CSF. The hepatotoxic potential of the growth factors is not clearly established, but the occurrence of coagulation abnormalities has recently been reported. Renal and biological disturbances are usually transient. Long term treatment with GM-CSF and G-CSF also seems to be well tolerated, but the possible occurrence of several adverse events, i.e. bone disorders, leukaemia, unmasking or acceleration of underlying disease, require further investigation in patients receiving prolonged treatment, as in myelodysplasia. Finally, antibodies against growth factors have been reported only with GM-CSF. Other cytokines are still under investigation. Flu-like and constitutional symptoms, sometimes dose-limiting, have been reported with IL-1, IL-3, IL-4 and IL-6, while M-CSF was occasionally associated with such adverse effects. More specific adverse events, also frequently considered as dose-limiting toxicities, include hypotension with IL-1, severe headache or skin rash with IL-3, and nasal congestion and gastroduodenal lesions with IL-4. Severe capillary leak syndrome has been reported only with IL-4. M-CSF toxicity is minimal and limited to reversible but sometimes dose-limiting thrombocytopenia and ophthalmological symptoms with the recombinant product. Again, the safety of long term administration of these cytokines has not yet been determined, and IL-3-induced disease progression in myelodysplastic patients has been suggested.
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PMID:Clinical toxicity of cytokines used as haemopoietic growth factors. 865 81

In order to assess the efficacy and safety of recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in the treatment of HIV-associated leukopenia, 35 subjects suffering from severe leukopenia/neutropenia (24 with a previous diagnosis of AIDS, 11 with AIDS-related complex), received rHuGM-CSF at 0.5-3 micrograms/Kg/day subcutaneously for a mean period of 9.7 +/- 12.5 weeks (range 2-43 weeks). Five patients have been treated continuously for more than 6 months. rHuGM-CSF administration led to a significant (at least two-fold; P < .001) increase in total leukocyte, neutrophil and monocyte count by the second week of treatment, subsequently maintained through the entire course of therapy. No considerable effects on other hematological, immunological and virological parameters have been detected. Patients treated with rHuGM-CSF did not suffer from novel opportunistic diseases, while bacterial infections occurred in only 3 cases (pneumonia in 2, otitis/mastoiditis in 1). Long-term treatment with rHuGM-CSF allowed continuation or resumption of potentially myelotoxic drugs in 22 patients out of 35. A self-limited flu-like syndrome represented the most common adverse event (observed in 15 patients), while no other significant clinical or laboratory abnormalities were found. In conclusion, long-term rHuGM-CSF therapy showed a good efficacy and safety profile in the treatment of HIV-related leukopenia, also increasing tolerability to potentially myelosuppressive drugs, and leading to a significant reduction in morbidity due to secondary infections.
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PMID:Recombinant human granulocyte-macrophage colony-stimulating factor (rHuGM-CSF) in leukopenic patients with advanced HIV disease. 880 19

Bronchial epithelial cells are primary sites of airway viral infection, and these cells may play an important role in the pathogenesis of respiratory diseases. It has recently been reported that bronchial epithelial cells express RANTES. RANTES attracts monocytes, T cells, eosinophils, and basophils; it can also activate eosinophils. To determine whether viral infection induces RANTES expression on bronchial epithelial cells, we infected a bronchial epithelial cell line, NCI-H292, with influenza virus A (H3N2). We then examined the concentration of RANTES in the culture medium of infected cells by ELISA and assessed expression of the gene for RANTES by the reverse-transcriptase polymerase chain reaction. We also investigated the concentrations of IL-6, IL-8, and granulocyte-macrophage colony-stimulating factor in the medium of infected cells, because some virus infections have been reported to induce expression of these cytokines on bronchial epithelial cells, but there are few data concerning influenza virus infection. Small amounts of IL-6 and IL-8 were detected in the medium of uninfected cells. RANTES was not detected in the medium of uninfected cells. After influenza virus infection, significant amounts of IL-6, IL-8, and RANTES were released into the culture medium of infected cells, and RANTES messenger RNA was detected from infected cells. Granulocyte-macrophage colony-stimulating factor was not detected in the medium of uninfected and infected cells. These results suggest that influenza virus infection may stimulate production of IL-6, IL-8, and RANTES from human bronchial epithelial cells and that these cytokines may contribute to the pathogenesis of airway inflammatory diseases caused by influenza virus infection.
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PMID:Expression of IL-6, IL-8, and RANTES on human bronchial epithelial cells, NCI-H292, induced by influenza virus A. 897 9

HLA class I and II molecules play a central role in regulating host immune responses against microbial infections because they present foreign antigens to CD8+ and CD4+ T lymphocytes, respectively. Many cytokines, especially interferons (IFN), are known to upregulate human leucocyte antigen (HLA) class I and II gene expression, but the kinetics, expression levels and viral regulation of HLA genes in primary human cells have not been well documented. Stimulation of peripheral blood mononuclear cells (PBMC) with IFN-alpha and IFN-gamma resulted in a 1.5- to twofold increase in HLA class I and beta 2-microglobulin expression in lymphocytes and monocytes. Lymphocytes did not express any detectable HLA class II either basally or after IFN induction. In monocytes, instead, a high basal class II expression was found and it was further induced by IFN-alpha (up to twofold) and especially by IFN-gamma (up to fivefold). In granulocyte-macrophage colony-stimulating factor (GM-CSF) differentiated human macrophages, basal HLA class I and II protein expression levels were high but IFN-gamma stimulation was able to further enhance their expression. Accordingly, class I and II mRNA expression was elevated by IFN-gamma, whereas IFN-alpha practically had no effect on HLA class I mRNA levels. Influenza A virus infection of macrophages resulted in temporary increases in HLA class I, beta 2-microglobulin and class II antigen expression. Neutralization of virus-induced IFN production by antibodies against type I and II IFNs prevented the virus-induced upregulation of HLA antigens. At late times of infection, as analysed by steady-state mRNA expression, both HLA class I and II mRNA were strongly reduced. These results suggest that IFNs are important regulators of HLA genes and responsible for a temporary increase in HLA antigen expression during influenza A virus infection.
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PMID:Regulation of HLA class I and II expression by interferons and influenza A virus in human peripheral blood mononuclear cells. 930 32

Recent experimental data have shown that mice could be immunized efficiently, in particular against cancer, by the injection of antigen-loaded dendritic cells (DC) or macrophages (MPH). In the present work, these two antigen-presenting cells (APC) were prepared in humans from circulating mononuclear cells (MNC). MPH were obtained from MNC that were cultured in hydrophobic plastic bags and purified by elutriation. DC were from the culture of adherent elutriation-purified monocytes in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). The two APC were prepared in parallel from the same donors and their phenotype and antigen-presenting capacity were compared. DC differed from MPH by a higher expression of HLA-DR and CD23 and a lower expression of CD14, CD64 and of adhesion molecules. DC and MPH were comparably effective in (a) enhancing the mitotic response of autologous lymphocytes to immobilized anti-CD3 (accessory function); (b) presenting melanoma peptides to specific cytotoxic T lymphocyte (CTL) clones; and (c) stimulating the generation of CTL directed against a myxovirus influenza peptide. However, DC were more effective than MPH in inducing the mitotic response of allogeneic peripheral blood leucocytes (PBL), possibly because of their higher expression of HLA class II molecules. In conclusion, DC and MPH prepared from blood MNC did not differ substantially in their ability to activate HLA class I-restricted T-cell responses by exogenous peptide presentation.
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PMID:Human monocyte-derived macrophages and dendritic cells are comparably effective in vitro in presenting HLA class I-restricted exogenous peptides. 937 6

A variety of approaches to antitumor therapy are currently being explored that use both antigen-encoding DNA and noncoding nucleotides as a component of gene vaccination. Among the specific strategies reviewed are a construct that fuses a single-chain variable fragment (scFv) that incorporates both the variable-region genes necessary to encode the idiotypic determinants with fragment C (FrC) of tetanus toxin; a novel vector system using herpes simplex virus 1 (HSV-1) for in vivo gene delivery; the possibility of eliciting hyperacute xenograft response to treat human cancer; and the use of gene gun-mediated granulocyte-macrophage colony-stimulating factor (GM-CSF) cDNA-based tumor cell vaccines. The protection provided by DNA vaccination against viral diseases such as influenza suggested a role for such vaccines against cancer. However, unlike vaccines against infectious diseases, cancer vaccines are therapeutic, rather than prophylactic. With multiple myeloma, for example, it is possible that the optimal timing of administration of such a vaccine is during a remission that has been induced by traditional therapies, to eliminate residual disease. DNA cancer vaccines are designed to activate immune responses to tumor antigens to which the immune system has already been exposed. To do so, the vaccines must first overcome immune tolerance that may have already developed to the tumor. There is increasing evidence that tumor antigens, unlike viral or bacterial antigens, do not consistently activate an immune response. One major factor in determining whether a reaction occurs appears to be whether antigen presentation is accompanied by danger signals. With viral or bacterial infection, the accompanying tissue destruction and inflammation produce costimulatory signals that promote T-cell activation. However, inflammatory and tissue-destructive processes are absent during initial tumor transformation. The typical outcome may be immunologic tolerance.
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PMID:DNA vaccination against multiple myeloma. 998 89

The coadministration of cytokines can modulate immunity in DNA based viral vaccines. In order to determine the effects of various cytokines on long-term protection against the influenza virus, mice were intramuscularly coinoculated with plasmids that encoded either the granulocyte-macrophage colony-stimulating factor (GMCSF), interleukin-4 (IL-4), interleukin-12 (IL-12), or the interleukin-6 (IL-6) gene, in the presence of two plasmids that encoded the nucleoprotein (NP) and the hemagglutinin (HA) gene of the influenza A virus. The coadministration of IL-4, IL-6 and IL-12 transiently enhanced antibody responses against influenza virus in early time points (4 to 7 week post immunization) after post inoculation. The expression of GMCSF gene resulted in the sustained elevation of antibody responses for at least 20 weeks post inoculation. However, NP-specific CTL responses decreased in these animals. Mice that received either the IL-12 or the IL-6 gene had enhanced NP-specific CTL responses. Remarkably, the coadministration of the IL-6 gene completely protected mice from a lethal challenge with influenza virus. Conversely, mice that received the IL-4 gene appeared to be more susceptible to lethal challenge than mice that were inoculated with the NP and the HA genes alone. These results demonstrate that the use of cytokines as molecular adjuvants when coadministered in influenza DNA vaccination must be specific. Our data also demonstrates that the coadministration of IL-6 should be considered to enhance the efficacy of influenza DNA vaccines.
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PMID:IL-6 induces long-term protective immunity against a lethal challenge of influenza virus. 1007 28

The aim of this study was to improve the potency of the currently used influenza subunit vaccines, which are of relatively low efficiency in high-risk groups. Influenza A virus (Shangdong/9/93) haemagglutinin/neuraminidase (H3N2), granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-2) were encapsulated, each separately or combined, in multilamellar vesicles composed of dimyristoyl phosphatidylcholine. BALB/c mice were immunized once, i.p. or s.c., with 0.05-2.0 microg HN administered either as free antigen (F-HN), adsorbed to aluminum hydroxide (Al-HN), or encapsulated in liposomes (Lip-HN), separately or together with 1 x 10(2)-4.5 x 10(4) units of free or encapsulated cytokines. Serum antibodies were assayed on days 11-360 by the haemagglutination-inhibition (HI) test and ELISA. Protective immunity against intranasal virus challenge was determined at 9-14 months post-vaccination. The following results were obtained: (1) The efficiency of encapsulation in liposomes was 95, 90 and 38% for HN, IL-2 and GM-CSF, respectively, and the liposomal preparations were highly stable as an aqueous dispersion for > 2 months at 4 degrees C. (2) Following immunization with 0.5 microg Lip-HN, there was an earlier, up to 50-fold stronger, and 3-5 times longer response than that obtained with nonliposomal HN. (3) Coimmunization with free cytokines further increased the response 2-20 times and the two cytokines had an additive effect. (4) Liposomal cytokines were 2-20 times more effective than the free cytokines and their stimulatory effect was more durable. (5) A 100% seroconversion (HI titer > or = 40) was achieved with only 10-25% of the routinely used antigen dose, by encapsulating either antigen or cytokine. (6) The level of protection following vaccination with the combined liposomal vaccines was 70-100% versus 0-25% in mice immunized with Al-HN alone, and no toxicity was observed. In conclusion, our animal experiments show that the liposomal vaccines are superior to the currently used influenza vaccines, increasing the response by 2-3 orders of magnitude in mice. This approach may also prove valuable for subunit vaccines against other microorganisms.
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PMID:A novel influenza subunit vaccine composed of liposome-encapsulated haemagglutinin/neuraminidase and IL-2 or GM-CSF. I. Vaccine characterization and efficacy studies in mice. 1019 36

This study compared two recombinant human (rh) hematopoietic growth factors in healthy volunteers for stem cell stimulation. Granulocyte colony-stimulating factor (G-CSF, n=9) or granulocyte-macrophage colony-stimulating factor (GM-CSF, n=8) was given subcutaneously for 5 days (5 microg/kg/day). Controls (n=5) received no growth factor. Laboratory parameters and side effects were monitored for 8 days. Within 24 h, both cytokines led to a rapid increase of leukocytes, the majority of which were granulocytes. Compared with the controls (n=5), the increase on day 5 in the G-CSF/GM-CSF groups was 37-/10-fold (CD34+ cells), 5.2-/2.4-fold (leukocytes), 7.2-/3.0-fold (granulocytes), 7.4-/4.4-fold (monocytes), 1.7-/1.1-fold (lymphocytes), 9.8-/2.7-fold (basophils), 2.3-/9.6-fold (eosinophils), and 1.9-/1.6-fold (reticulocytes). The mobilization of myeloblasts, promyelocytes, myelocytes, and metamyelocytes coincided with the pronounced increase of CD34 + PBPC observed on day 4. Serum levels of uric acid (UA) and lactic dehydrogenase (LDH) increased under G-CSF, and platelets decreased after G-CSF discontinuation. Rash at the injection site occurred in 50% of the GM-CSF-treated volunteers. Seven volunteers in the GM-CSF group and six in the G-CSF cohort complained of flu-like symptoms, including musculoskeletal pain. We conclude that, in terms of tolerance and mobilization of CD34+ cells and leukocytes, G-CSF is superior to GM-CSF, but higher levels of UA and LDH and late decrease in platelets make monitoring of these parameters necessary.
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PMID:G-CSF versus GM-CSF for stimulation of peripheral blood progenitor cells (PBPC) and leukocytes in healthy volunteers: comparison of efficacy and tolerability. 1021 53


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