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)

It is now generally accepted that many cytokines are involved in the pathogenesis of autoimmune disease, either directly by causing tissue destruction or indirectly through the activation of autoreactive and inflammatory cells. Thus, cytokines, such as tumor necrosis factor-alpha, are implicated in the pathogenesis of rheumatoid arthritis based on in vitro studies on synovial tissue from patients with rheumatoid arthritis, which suggest that the effects of tumor necrosis factor-alpha are amplified by its potential to induce other pro-inflammatory cytokines, such as interleukin-1 and granulocyte-macrophage colony-stimulating factor. Transgenic mouse technology has shown that mice expressing the human tumor necrosis factor-alpha gene develop a polyarthritis. Interleukin-2 has also been identified by transgenic technology as a cytokine involved in the pathogenesis of insulin-dependent diabetes mellitus through the activation and stimulation of growth of autoreactive T cells.
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PMID:Cytokines in autoimmunity. 146 99

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.
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PMID:Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer. 910 57

The B cell line, MRL159.5, was established by somatic hybridization between splenic MRL/MP-lpr/lpr (lpr) mice B cells and 2.52M, a hypoxanthine-aminopterine-thymidine (HAT) medium-sensitive B cell line mutant. It possessed a receptor molecule for mouse erythrocytes treated with bromelain (Br-MRBC) on its surface, likely to be an autoreactive B cell clone specific for Br-MRBC as detected by rosette-forming assay with Br-MRBC. MRL159.5 spontaneously produced IL-6 and secreted IgM, and was induced to augment IgM secretion when treated with Br-MRBC or IL-6. Triggering of CD40 led to an augmentation of IgM secretion as well as IL-6 expression. Blocking the binding of IL-6 to its cellular receptor through the use of inhibitory antibodies inhibited CD40-induced IgM secretion, suggesting a possible autocrine role of IL-6 for CD40-induced differentiation of this B cell hybridoma. Addition of IL-4 or Br-MRBC augmented IL-6 expression as well as IgM secretion by CD40-activated MRL159.5 cells. CD40 also augmented tumour necrosis factor-alpha (TNF-alpha) and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression but resulted in decreased IL-10 expression. Furthermore, under conditions where IL-6 expression was augmented, IL-6R alpha (gp80) expression was down-regulated, suggesting a negative feedback mechanism of an IL-6 autocrine loop in this hybridoma. These results demonstrate a role by which T cell-dependent activation through CD40 regulates an IL-6 autocrine loop, controlling differentiation of autoreactive B cells in autoimmune disease.
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PMID:Regulation of cytokine expression by an autoreactive B cell clone derived from MRL/MP-lpr/lpr mice. 976 95

Assessing the functionality of T lymphocytes is important in determining progression rate in human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS), transplant rejection, and autoimmune disease. Activation of T-cells in response to antigen results in expression of cytokines and cytokine receptors, proliferation, and development of effector function. Multiplexed flow cytometric analyses were developed to measure cytokine receptor expression, internal cytokine expression, and cytokine secretion by activated T-cells in vitro. Receptor expression was determined by the binding of phycoerythrin-labeled cytokines. Internal cytokine was determined by intracellular labeling with anti-cytokine antibodies. Cytokine secretion was determined by a flow cytometry-based immunofluorescence assay. The assays could be multiplexed, measuring up to six cytokines simultaneously and measuring cellular receptor expression simultaneously with cytokine secretion. The immunoassays were sensitive in the femtomolar range, allowing determination of normal serum levels of cytokines (<100 fg/ml). Using granulocyte-macrophage colony-stimulating factor (GM-CSF) secretion as a marker for activation, it was determined that at peak secretion (68 h post activation) an average of 1,150 molecules of GM-CSF were produced per cell per hour. Active infection with several viruses reduced the ability of T-cells to be activated. Activated T-cells (1 x 10(6)) normally produced 4-8 pg/ml/h GM-CSF after 20 h of activation, impaired T-function resulted in a decrease to the 0.2-2.0 pg/ml/h range.
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PMID:T-lymphocyte functionality assessed by analysis of cytokine receptor expression, intracellular cytokine expression, and femtomolar detection of cytokine secretion by quantitative flow cytometry. 977 87

Monocytes can differentiate into dendritic cells (DC), cells with a pivotal role in both protective immunity and tolerance. Defects in the maturation or function of DC may be important in the development of autoimmune disease. We sought to establish if there were differences in the cytokine (granulocyte-macrophage colony-stimulating factor and IL-4)-driven maturation of monocytes to DC in patients with MS and whether drugs used to treat MS affected this process in vitro. We have demonstrated that there is no defect in the ability of magnetic activated cell sorting (MACS)-purified monocytes from patients with MS to differentiate to DC, but equally they show no tendency to acquire a DC phenotype without exogenous cytokines. Interferon-beta1a prevents the acquisition of a full DC phenotype as determined by light and electron microscopy and by flow cytometry. Methylprednisolone not only prevents the development of monocyte-derived DC but totally redirects monocyte differentiation towards a macrophage phenotype. Evidence is evolving for a role for DC in central nervous system immunity, either within the brain or in cervical lymph nodes. The demonstrated effect of both drugs on monocyte differentiation may represent an important site for immune therapy in MS.
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PMID:Monocyte-derived dendritic cells: a potential target for therapy in multiple sclerosis (MS). 1120 59

Pulmonary alveolar proteinosis (PAP; the accumulation of surfactant lipids and proteins in the alveoli) has a number of infectious and environmental causes but is usually idiopathic. The clinical presentation of PAP is nonspecific; thus, the diagnosis is frequently missed, leading to inappropriate therapy and unnecessary morbidity. Recent advances suggest that a deficiency in granulocyte-macrophage colony-stimulating factor (GM-CSF) activity may lead to this surfactant accumulation. Anti-GM-CSF antibodies have been found in PAP patients, fueling speculation that PAP may be an autoimmune disease. These findings are being translated into novel forms of therapy.
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PMID:Our new understanding of pulmonary alveolar proteinosis: what an internist needs to know. 1176 22

A phase I study of granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced tumor vaccine for patients with metastatic renal cell carcinoma (RCC) was initiated in 1998, as the first cancer gene therapy in Japan. The study is still ongoing, but the first patient is presented here as a case report. The patient was a 60-year-old man with Stage IV CRC with multiple lung metastases. After surgical resection of the tumor, autologous tumor cells were transduced and cultured to produce GM-CSF. The patient received a total of 2.2 x 108 gene-transduced autologous vaccine cells by subcutaneous injection. During the course of vaccination, growth of the largest metastatic mass slowed to some extent; however, multiple new lesions developed. About 1 month after the start of low-dose IL-2 therapy, rapid and remarkable regression in a large lung hilar metastatic mass was noticed. The patient died of progressive disease 7 months after the start of GM-CSF gene therapy. Careful histological examination by autopsy revealed that the responding mass was infiltrated by CD8 positive dominant T lymphocytes, and did not exhibit vasculitis or any other changes associated with active autoimmune disease.
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PMID:Advanced renal cell carcinoma treated with granulocyte-macrophage colony-stimulating factor gene therapy: a clinical course of the first Japanese experience. 1222 44

Pulmonary alveolar proteinosis (PAP) is a rare disease characterized by the accumulation of phospholipids and surfactant proteins in the lung. The central role for granulocyte-macrophage colony-stimulating factor (GM-CSF) in surfactant homeostasis has been established in mice lacking the GM-CSF gene, which results in murine pulmonary alveolar proteinosis. No GM-CSF gene defect has been defined in adult patients with idiopathic PAP. Previous studies indicated that the human disease differs from the murine model by the presence of circulating, neutralizing autoantibodies against GM-CSF. Therefore, the final common pathway between the GM-CSF knockout and human PAP appears to be the deficiency of functionally active GM-CSF. In the present study, all patients with idiopathic PAP were found to have systemic and localized antibodies against GM-CSF. Anti-GM-CSF titers were a specific and sensitive marker for PAP. In addition, we present data showing that the absence of active GM-CSF is associated with enhanced levels of macrophage colony-stimulating factor, monocyte chemoattractant protein-1, and interleukin-8. These studies confirm and strengthen previous studies and support the concept that adult idiopathic PAP is an autoimmune disease defined by the presence of anti-GM-CSF. Further, using anti-GM-CSF as an indicator of pulmonary alveolar proteinosis may avoid the use of more invasive means of evaluating patients with pulmonary disease characterized by alveolar infiltrates.
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PMID:Autoantibodies against granulocyte macrophage colony-stimulating factor are diagnostic for pulmonary alveolar proteinosis. 1235 82

Carcinoembryonic antigen (CEA) is a glycoprotein that is normally expressed in certain parts of the body and commonly overexpressed in most carcinomas of the colon, rectum, breast, lung, pancreas, and gastrointestinal tract. Increased expression of CEA promotes increased intercellular adhesions, which may lead to metastasis. Carcinoembryonic antigen is often used as a serologic marker of malignancy because of its overexpression in cancer as well as its measurability in serum. However, because CEA is normally expressed in the body, the immune system commonly becomes tolerant to it. If this tolerance can be overcome without leading to autoimmune disease, CEA vaccination therapy could be immensely beneficial to cancer patients. A number of preclinical and clinical studies have been conducted on the use of recombinant CEA-vaccinia virus vaccines and recombinant ALVAC-CEA vaccines. In general, the vaccines have been well tolerated and effective at inducing CEA-specific cytotoxic T-cell responses, especially when used in the presence of the T-cell costimulatory molecule B7.1. "Prime and boost" techniques combining both types of vaccines and the addition of cytokines such as granulocyte-macrophage colony-stimulating factor have resulted in enhanced T-cell responses. The combination of vaccinia or ALVAC vaccines with a triad of costimulatory molecules (B7.1, ICAM-1, and LFA-3) has also stimulated significant T-cell increases. This review summarizes these studies and discusses the role of CEA in cancer immunotherapy.
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PMID:Carcinoembryonic antigen-based vaccines. 1288 10

Pulmonary alveolar proteinosis (PAP) is characterized by the accumulation of surfactant phospholipids and proteins within the lung alveoli. Important advances have been made over the past 8 years in our understanding of this disease, offering new directions for research and patient care. First, genetically altered mice that are homozygous for a disrupted granulocyte-macrophage colony-stimulating factor (GM-CSF) gene developed a lung lesion with histologic resemblance to PAP. The surfactant is thought to be catabolized or cleared mostly by alveolar macrophages, this process being dependent on GM-CSF. Second, a neutralizing autoantibody against GM-CSF was found in serum and bronchoalveolar lavage fluid of patients with idiopathic PAP but not in healthy controls, thereby raising the suspicion that human PAP may be an autoimmune disease. The relationship between the antibody and disease pathogenesis remains unclear but data suggest that the GM-CSF antibody may have a potential role as a diagnostic test. No specific therapy exists for PAP. Sequential whole lung lavage is the standard of care. Exogenous therapy with GM-CSF may improve the lung disease in some patients with PAP but this therapy is still experimental. Interventions directed at treating a relative GM-CSF deficiency by administration of GM-CSF or lowering the antibody level (i.e. by plasmapheresis or immunosuppression) may hold promise as future therapy for this rare disease.
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PMID:Pulmonary alveolar proteinosis. Clinical manifestations and optimal treatment strategies. 1535 Jan 60


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