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)

Immunization with tumor-associated antigen pulsed dendritic cells (DC) has been shown to elicit both protective and therapeutic antitumor immunity in a variety of animal models and is currently being investigated for the treatment of cancer patients in clinical trials. In this study we show that DC can be generated from peripheral blood mononuclear cells of healthy donors as well as breast and melanoma cancer patients using granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-13 (IL-13) and that these DC have many of the same characteristics as DC differentiated using GM-CSF and IL-4. The DC generated in GM-CSF and IL-13 are CD14- and express high levels of the cell surface markers CD86, HLA-DR, and CD58, as do DC generated in GM-CSF and IL-4. The purity and yield of both DC populations are not significantly different. Furthermore, both populations of DC are effective at presentation of alloantigen as determined in a mixed lymphocyte response, and both are able to process and present soluble tetanus toxoid antigen to CD4+ T cells. Because we are interested in the generation of DC for antigen-specific cytotoxic T lymphocyte (CTL) generation, we compared the ability of peptide-pulsed DC differentiated in GM-CSF and IL-4 versus GM-CSF and IL-13 for the generation of influenza and MART-1 specific CTL. Both populations of DC induced CD3+ CD8+ CD4- and CD56- CTL, which could lyse the appropriate targets in an antigen-specific manner. Finally, both GM-CSF and IL-4 DC and GM-CSF and IL-13 DC yielded similar beta galactosidase expression levels after transduction with recombinant adenovirus containing the LacZ gene. These results suggest that DC generated in GM-CSF and IL-13 may be useful for immunotherapy and gene therapy protocols.
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PMID:IL-13 can substitute for IL-4 in the generation of dendritic cells for the induction of cytotoxic T lymphocytes and gene therapy. 1033 82

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the serological response at influenza vaccination was studied in 117 patients who had undergone stem cell transplantation (SCT). The vaccine response was evaluated as significant increases in levels of influenza hemagglutination-inhibition (HAI) antibodies and of IgG antibodies measured by enzyme-linked immunosorbent assay (ELISA). There was no difference in antibody response to either influenza A or B in 64 patients who received GM-CSF at vaccination, compared with the 53 who did not. In the subgroup of allogeneic SCT patients, HAI showed that the response rate to the influenza B vaccine was significantly higher in the treatment group (P<.05). ELISA showed that autologous SCT patients with breast cancer who received GM-CSF had a better response to influenza A (P<.05) and B (P<.01). At early vaccination, 4-12 months after stem cell transplantation, these responses were more pronounced. GM-CSF appears to improve the response to influenza vaccination in some groups of SCT patients, but only to a limited extent.
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PMID:Granulocyte-macrophage colony-stimulating factor as immunomodulating factor together with influenza vaccination in stem cell transplant patients. 1067 39

It was observed that interferon beta (IFN-beta) prevents the down-regulation of the interleukin-3 receptor alpha chain (IL-3Ralpha), which spontaneously occurs during culture of human monocytes. The functionality of IL-3R was demonstrated by the fact that IL-3 rescued IFN-beta-treated monocytes from apoptosis. Monocytes cultured in the presence of IFN-beta and IL-3 acquire a dendritic morphology and express high levels of HLA antigen class I and class II and costimulatory molecules. When stimulated by either lipopolysaccharide or fibroblasts expressing CD40 ligand (CD40L) transfectants, dendritic cells (DCs) generated in IFN-beta and IL-3 secreted high levels of IL-6, IL-8, and tumor necrosis factor-alpha but low levels of IL-12 in comparison with DCs generated in IL-4 and granulocyte-macrophage colony-stimulating factor (GM-CSF). In mixed leukocyte culture, IL-3-IFN-beta DCs induced a vigorous proliferative response of allogeneic cord blood T cells and elicited the production of high levels of IFN-gamma and IL-5 by naive adult CD4+ T cells. Finally, IL-3-IFN-beta DCs were found to produce much higher levels of IFN-alpha than IL-4-GM-CSF DCs in response to Poly (I:C) but not to influenza virus. It was concluded that monocytes cultured in the presence of IL-3 and IFN-beta differentiate into DCs with potent helper T-cell stimulatory capacity despite their low secretion of IL-12.
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PMID:Interleukin-3 and interferon beta cooperate to induce differentiation of monocytes into dendritic cells with potent helper T-cell stimulatory properties. 1180 4

To investigate the adjuvant capacity of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon (IFN-gamma), we cloned these rhesus cytokines into a mammalian expression vector. Two groups of six rhesus macaques (Macaca mulatta) received intradermal immunizations of plasmid DNA coding for SIV Eng and Gag, and influenza virus nucleoprotein (Flu-NP), with or without the co-administration of plasmid DNA coding for these cytokines. Humoral immune responses to antigens of both of these viruses and SIV specific T cell proliferative responses were significantly enhanced by co-immunization with the cytokines. These twelve monkeys, and a group of six naive controls, were challenged by the oral mucosal route with the uncloned and highly pathogenic SIVmac251. All monkeys became infected. The early CD4 decline was reduced in the group co-immunized with cytokine and viral plasmids. Unexpectedly, plasma viremia set points were not different in this co-immunized group and the non-immunized control group. On the other hand, monkeys vaccinated with equivalent amounts of empty vector plasmid (i.e. no cytokine inserts) along with plasmids expressing viral antigens demonstrated a slight but significant decrease in acute viremia compared to non-immunized controls (P<0.02). However, viral loads at set points were not significantly different between both the immunized and the non-immunized control group. Thus, although the cytokine vectors demonstrated detectable enhancement of the immune response to different viral antigens, such enhanced response did not translate into better anti-viral control in our experiment. These results underscore the need for further testing of cytokines as vaccine adjuvants in relevant animal models.
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PMID:Co-immunization of rhesus macaques with plasmid vectors expressing IFN-gamma, GM-CSF, and SIV antigens enhances anti-viral humoral immunity but does not affect viremia after challenge with highly pathogenic virus. 1247 32

New or improved vaccines against viruses such as influenza, parainfluenza types 1-3, measles, dengue, and respiratory syncytial virus would prevent an enormous burden of morbidity and mortality. Vaccines or vaccine candidates exist against these viral diseases, but all could potentially be improved if the immunogenicity of the vaccine could be enhanced. We found that the immunogenicity in primates of a live-attenuated vaccine candidate for parainfluenza virus type 3, an enveloped RNA virus that is an important etiologic agent of pediatric respiratory tract disease, could be enhanced by expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) from an extra gene inserted into the genome of a cDNA-derived virus. Expression of GM-CSF by the live attenuated recombinant virus did not per se affect the level of pulmonary viral replication in rhesus monkeys after topical administration, which was 40-fold lower than that of WT parainfluenza virus type 3. Despite that, the expressed extra gene augmented the virus-specific serum antibody response to a level that was (i) 3- to 6-fold higher than that induced by the same virus with an unrelated RNA insert of equal length and (ii) equal to the response induced by nonattenuated WT virus. In addition, topical immunization with the attenuated virus expressing GM-CSF induced a greater number of virus-specific IFN-gamma-secreting T lymphocytes in the peripheral blood of monkeys than did immunization with the control virus bearing an unrelated RNA insert. These findings show that the immunogenicity of a live-attenuated vaccine virus in primates can be enhanced without increasing the level of virus replication. Thus, it might be possible to develop live-attenuated vaccines that are as immunogenic as parental WT virus or, possibly, even more so.
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PMID:More antibody with less antigen: can immunogenicity of attenuated live virus vaccines be improved? 1248 28

Arguments exist as to the cause of chronic fatigue syndrome (CFS). Some think that it is an example of symptom amplification indicative of functional or psychogenic illness, while our group thinks that some CFS patients may have brain dysfunction. To further pursue our encephalopathy hypothesis, we did spinal taps on 31 women and 13 men fulfilling the 1994 case definition for CFS and on 8 women and 5 men serving as healthy controls. Our outcome measures were white blood cell count, protein concentration in spinal fluid, and cytokines detectable in spinal fluid. We found that significantly more CFS patients had elevations in either protein levels or number of cells than healthy controls (30 versus 0%), and 13 CFS patients had protein levels and cell numbers that were higher than laboratory norms; patients with abnormal fluid had a lower rate of having comorbid depression than those with normal fluid. In addition, of the 11 cytokines detectable in spinal fluid, (i) levels of granulocyte-macrophage colony-stimulating factor were lower in patients than controls, (ii) levels of interleukin-8 (IL-8) were higher in patients with sudden, influenza-like onset than in patients with gradual onset or in controls, and (iii) IL-10 levels were higher in the patients with abnormal spinal fluids than in those with normal fluid or controls. The results support two hypotheses: that some CFS patients have a neurological abnormality that may contribute to the clinical picture of the illness and that immune dysregulation within the central nervous system may be involved in this process.
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PMID:Spinal fluid abnormalities in patients with chronic fatigue syndrome. 1564 84

Acute mucositis is dose-limiting in many accelerated radiotherapy schedules for head and neck cancer. Cytokines may be one means of reducing the severity of mucositis. A study was designed to assess the effect of subcutaneous molgramostin (granulocyte-macrophage colony stimulating factor; GM-CSF) injections on acute radiation morbidity in patients undergoing accelerated radiotherapy for laryngeal cancer. A prospective, randomized, observer-blind, controlled trial was conducted in 29 patients who were to receive radical radiotherapy over 3 weeks for early stage laryngeal cancer. Patients were randomized to receive 150 microg (approximately 2 microg kg(-1)) GM-CSF subcutaneously once daily for 14 days after the second week of radiotherapy, or no GM-CSF. Patients were assessed weekly for grade of mucositis, skin reactions and related parameters. The severity of mucositis was reduced in the GM-CSF arm (p<0.05). No other end-points reached statistical significance. Two patients failed to complete their courses of GM-CSF. Three developed influenza type symptoms and in one an allergic reaction was noted. There was no difference in tumour control rates. Subcutaneous GM-CSF reduced the severity of mucositis in patients undergoing accelerated radiotherapy. Injections were well tolerated. Further studies of cytokines are warranted, to assess the feasibility of increasing the total doses of accelerated radiotherapy given, with the aim of improving tumour cure rates.
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PMID:Randomized phase II study of GM-CSF to reduce mucositis caused by accelerated radiotherapy of laryngeal cancer. 1682 67

GVAX cancer immunotherapies are composed of whole tumor cells genetically modified to secrete the immune stimulatory cytokine, granulocyte-macrophage colony-stimulating factor (GM-CSF), and then irradiated to prevent further cell division. Both autologous (patient specific) and allogeneic (non-patient specific) GVAX platforms have been evaluated either as single agents or in combination with other immunomodulatory strategies. Many early-phase clinical trials have now been completed. Results have consistently demonstrated a favorable safety profile manifested primarily by injection site reactions and flu-like symptoms. Consistent evidence of immune activation and clinical activity, including radiologic tumor regressions, has been seen across multiple cancer indications in both early- and late-stage disease. Phase 3 trials evaluating an allogeneic GVAX immunotherapy product in prostate cancer are under way.
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PMID:GM-CSF gene-modifed cancer cell immunotherapies: of mice and men. 1716 79

Coxiella burnetii is a highly infectious obligate intracellular bacterium. The phase I form is responsible for Q fever, a febrile illness with flu-like symptoms that often goes undiagnosed. The attenuated C. burnetii phase II (having a truncated "O" chain of its lipopolysaccharide) does not cause disease in immunocompetent animals; however, phase II organisms remain infectious, and we questioned whether disease could be produced in immunodeficient mice. To study C. burnetii phase II infections, febrile responses in gamma interferon knockout (IFN-gamma(-/-)), BALB/c, Toll-like receptor 2 knockout (TLR2(-/-)), and C57BL/6 mice were measured using the Nine Mile phase II (NMII) strain of C. burnetii. Immunocompetent mice showed minimal febrile responses, unlike those obtained with IFN-gamma(-/-) and TLR2(-/-) mice, which showed elevated rectal temperatures that were sustained for approximately 15 days with transient increases in splenic weights. Reinfection of IFN-gamma(-/-) and TLR2(-/-) mice with C. burnetii NMII 30 days after primary infection protected mice as evident by reduced febrile responses and a lack of splenic inflammation. Although minimal detection of Coxiella in TLR2(-/-) mouse spleens was observed, greater colonization was evident in the IFN-gamma(-/-) mice. Cytokine analysis was performed on infected peritoneal macrophages isolated from these mice, and immunocompetent macrophages showed robust tumor necrosis factor alpha, IFN-gamma, and granulocyte-macrophage colony-stimulating factor (GM-CSF) but no interleukin-12 (IL-12) responses. IFN-gamma(-/-) macrophages produced elevated levels of IL-6, IL-10, and IL-12, while TLR2(-/-) macrophages produced GM-CSF, IL-12, and minimal IL-10. To distinguish immunity conferred by innate or adaptive systems, adoptive transfer studies were performed and showed that immune lymphocytes obtained from immunocompetent mice protected against a subsequent challenge with NMII, indicating that adaptive immunity mediates the observed protection. Thus, our data show that NMII is capable of eliciting disease in immunocompromised mice, which may help in evaluation of vaccine candidates as well as the study of host-pathogen interactions.
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PMID:Attenuated Coxiella burnetii phase II causes a febrile response in gamma interferon knockout and Toll-like receptor 2 knockout mice and protects against reinfection. 1789 29

Influenza virus infection of the respiratory tract is characterized by a neutrophil infiltrate accompanied by inflammatory cytokine and chemokine production. We and others have reported that Toll-like receptor (TLR) proteins are present on human neutrophils and that granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment enhances IL-8 (CXCL8) secretion in response to stimulation with TLR ligands. We demonstrate that influenza virus can induce IL-8 and other inflammatory cytokines from GM-CSF-primed human neutrophils. Using heat inactivation of influenza virus, we show that viral entry but not replication is required for cytokine induction. Furthermore, endosomal acidification and viral uncoating are necessary. Finally, using single-cell analysis of intracellular cytokine accumulation in neutrophils from knockout mice, we prove that TLR7 is essential for influenza viral recognition and inflammatory cytokine production by murine neutrophils. These studies demonstrate neutrophil activation by influenza virus and highlight the importance of TLR7 and TLR8 in that response.
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PMID:Toll-like receptor-mediated activation of neutrophils by influenza A virus. 1854 85


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