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

Several antigens, including the products encoded by the genes MAGE-1 and MAGE-3, are recognized on human melanoma cells by HLA-A1, HLA-A2, or HLA-Cw*1601*-restricted T cells on autologous or HLA-matched melanoma cell lines. T-cell recognition of naturally processed MHC class I-presented peptides, or alternatively synthetic peptides derived from MAGE-1 or MAGE-3, leads to cytokine release as well as to a cytotoxic T-cell response in these antimelanoma-directed polyclonal or clonal effector T-cell populations. Recent reports suggest that the activity of T lymphocytes infiltrating melanoma in vivo appears to be impaired. We report here the characterization of the in vitro (in the presence of 6000 IU interleukin 2) expanded tumor-infiltrating lymphocyte (TIL) T-cell line PM2-B2 derived from a patient with rapidly progressing and therapy-resistant head and neck melanoma. The TIL cell line PM2-B2 did not lyse, but instead released granulocyte-macrophage colony-stimulating factor in response to the autologous tumor or HLA-A1-matched allogeneic tumor cell lines. The TIL line PM2-B2 did not kill the MHC class I natural killer/lymphokine-activated killer target cell lines Daudi or K562. The fine specificity of the TIL line PM2-B2 restricted by HLA-A1 was further characterized by evaluating specific granulocyte-macrophage colony-stimulating factor release in response to MHC class I-eluted peptides derived from HLA-A1(+) melanoma cell lines. TIL PM2-B2 failed to recognize the recently described HLA-A1-presented peptides derived from the gene products encoded by MAGE-1 or MAGE-3. PCR-based analysis of the freshly harvested tumor from patient PM2-B2 revealed the presence of message for the melanoma-associated gene products MAGE-1 and MAGE-3, but not for tyrosinase or MART-1/MELAN-A. Acid elution and high performance liquid chromatography fractionation of MHC class I-presented peptides from HLA-A1-matched melanoma cell lines 397 or 888 revealed that TIL PM2-B2 recognized at least three distinct peptide epitopes eluting in high performance liquid chromatographic bioactive fractions 5/6, 36, and 51/52. These bioactive peaks appeared to be shared among HLA-A1(+) melanoma cell lines. We suggest, based on this report, that HLA-A1-presented melanoma-derived peptides (other than those previously reported peptides derived from MAGE-1 or MAGE-3) may represent targets for TIL recognition as defined by cytokine release, but not cytotoxicity. Such an immune response differentially defined by cytokine release, but absent cytotoxic functions, may either reflect the impaired cytolytic function of the TIL population or reflect the inherent nature of HLA-A1-presented melanoma T-cell epitopes leading to cytokine release, but not to a cytotoxic T-cell response. Additionally, this report suggests that the individual T-cell immune response to melanoma may be rather complex, involving diverse T-cell effector functions (e.g., cytotoxicity or cytokine release), each of which should be evaluated in studies of antitumor-specific T-cell reactivity.
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PMID:Detection of naturally processed and HLA-A1-presented melanoma T-cell epitopes defined by CD8(+) T-cells' release of granulocyte-macrophage colony-stimulating factor but not by cytolysis. 981 95

Dendritic cells (DC) play a key role in the initiation of immune response by stimulating the naive T cells. The fate of DC after the initiation of immune response is not clearly understood. Although there are few reports implicating natural killer (NK) cells in the elimination of DC, killing of DC by LAK cells, and specifically by T cells, has not been studied. In this study, we observed that DC, generated from monocytes, in vitro in the presence of granulocyte-macrophage colony-stimulating factor, interleukin-4 (IL-4), and tumor necrosis factor alpha were susceptible to cytolysis by lymphokine-activated killer (LAK) cells induced in the presence of IL-2 and IL-15 but not IL-12 alone. However, LAK cells induced by a combination of IL-12 and suboptimal dose of IL-2 were cytotoxic to DC. When purified lymphocytes were activated with IL-2, the CD8+/CD57- fraction (T-LAK), but not the CD8-/CD57+ fraction (NK-LAK) was cytotoxic to autologous DC. However, when unseparated peripheral blood mononuclear cells were used to generate LAK cells, both T-LAK and NK-LAK fractions showed equal cytotoxicity against autologous DC. Monoclonal antibodies against CD54, CD11a, and CD18 significantly inhibited the cytolysis, indicating that the killing involves the engagement of CD54 with its ligands.
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PMID:Cytolysis of human dendritic cells by autologous lymphokine-activated killer cells: participation of both T cells and NK cells in the killing. 1038 Aug 97

Although malignant mesothelioma is not a classically immunogenic cancer, there is abundant evidence for immune recognition. The relative ease of obtaining tumor tissue makes mesothelioma ideal for studying surrogate biomarkers such as lymphocytic infiltration or expression of transduced genes. There is evidence that malignant mesothelioma patients as well as asbestos-exposed persons without mesothelioma have impaired immune responsiveness. Substantial progress has been made in animal models using several biological and immunological techniques, but clinical application has been problematic. Systems studied have included lysis by interleukin-2 (IL-2)-activated lymphokine-activated killer (LAK) cells, tumor necrosis factor-alpha (TNF-alpha), a p16-expressing adenovirus vector, suicide gene therapy using the herpes simplex virus-tyrosine kinase (HSV-tk) followed by ganciclovir, and immunomodulatory gene therapy with IL-2, IL-4, interferon-gamma (IFN-gamma), IFN-alpha, TNF-alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, and IL-1beta transfected into tumors. Vaccinia virus has been studied as a vector for cytokine gene transfer. Suicide gene therapy has been combined with a tumor vaccine. The University of Western Australia is initiating a pilot study of autologous vaccination in malignant mesothelioma. Novel agents under study include the angiogenesis inhibitors SU5416, bevacizumab, and thalidomide. ZD1839, an orally administered, highly selective inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, is being tested in a phase II trial. Since platelet-derived growth factor (PDGF) is thought to be an autocrine growth factor for mesothelioma STI-571 (Gleevec; Novartis, Basel, Switzerland), a highly selective inhibitor of the PDGF receptor tyrosine kinase, is being tested in a phase II trial. The development of more active cytotoxic combinations in this disease should facilitate further studies of chemoimmunotherapy. It seems likely that no single treatment modality will be effective by itself.
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PMID:New approaches for mesothelioma: biologics, vaccines, gene therapy, and other novel agents. 1183 73

Despite advances in locoregional chemotherapy, treatment of metastatic liver tumors remains a challenge. Since the liver is the largest organ of the reticuloendothelial system, locoregional immunotherapy would be a reasonable approach for the management of hepatic metastases. Indeed, various immunological approaches have been explored. Regional infusion of cytokines such as interleukin 2 (IL-2) or tumor necrosis factor-alpha (TNF-alpha) through the hepatic artery or the portal vein has been combined with chemotherapy and demonstrated to be better than chemotherapy alone. Locoregional adaptive immunotherapy (AIT) using lymphokine-activated killer (LAK) cells or tumor-infiltrating lymphocytes (TIL) has also been tried with rather disappointing responses. Addition of immunostimulants such as OK-432 to AIT increased clinical responses. Recently, several new approaches have emerged to improve the outcome of locoregional immunotherapy. Embolization of melanoma metastatic to the liver with a granulocyte-macrophage colony-stimulating factor (GM-CSF)/ethiodized oil emulsion resulted in control of liver metastases, as well as development of significant immune responses in remote extrahepatic metastases. A gene therapy designed to introduce foreign major histocompatibility complex (MHC) molecules in colorectal metastases has proven to be a safe and feasible approach. Larger scale clinical trials are mandatory to define the role of locoregional immunotherapy for metastatic tumors in the liver.
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PMID:Locoregional immuno(bio)therapy for liver metastases. 1195 Dec 14

Activation of macrophages and other immune components to release a series of proinflammatory cytokines is one of the first events in innate resistance to intracellular infections. Severe manifestations of tuberculosis (TB) could be caused by alterations in the balance of these cytokines. In this study, lymphokine-activated killer (LAK) cells of TB patients and normal individuals were generated by stimulation with cytokines in vitro. The LAK cells of both groups were further triggered with allogeneic tumor targets. Cytokines interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were estimated in the supernatants generated in the two groups. The aim was to see if infection with TB influenced the secretory capacity of the immune cells in vitro. Reduced cytokine profiles were observed in TB patients, indicating defective interactions between patient effector cells with allogeneic transformed cells compared with normal individuals. Partial restoration of IFN-gamma production was seen with a combination of cytokines interleukin-2 (IL-2) and IL-12 in TB patients. Based on the in vitro observations, we hypothesize that in vivo also there is diminished immune cell activation of effector cells in response to the presence of infected macrophages. This probably leads to a diminished secretory function that can be corrected by the use of such cytokines as IL-2 and IL-12. The effector populations of TB patients are probably in a state of target-induced anergy, allowing the bacteria to thrive, and immunomodulatory cytokines that improve the host immune response toward countering mycobacterial infection.
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PMID:Reduced cytokine secretions by LAK cells of pulmonary tuberculosis patients in response to tumor targets in vitro. 1216 71

Natural killer (NK) cell differentiation from pluripotent CD34(+) human hematopoietic stem cells or oligopotent lymphoid progenitors has already been reported. In the present study, long-term cultures of the CD56(-)/CD34(-) myeloid-like adherent cell fraction (ACF) from umbilical cord blood (UCB), characterized by the expression of CD14(+) as well as other myeloid markers, were set up with flt3 ligand (FL) and interleukin-15 (IL-15). The UCB/ACF gradually expressed the CD56 marker, which reached fairly high levels (approximately 90% of the cells were CD56(+)) by day 15. FL plus IL-15-driven ACF/CD56(+) cells progressively expressed a mature NK functional program lysing both NK- and lymphokine-activate killer (LAK)-sensitive tumor targets and producing high levels of interferon-gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor, tumor necrosis factor alpha, and IL-10 upon stimulation with IL-12 and IL-18. Similar results were obtained when highly purified CD14(+) cells from UCB were cultured with FL and IL-15. In contrast, UCB/CD34(+) cells cultured under the same conditions showed a delayed expression of CD56 and behaved functionally differently in that they exhibited NK but not LAK cytotoxicity and produced significantly fewer cytokines. Kinetic studies on the phenotype of UCB/ACF or UCB/CD14(+) cells cultured in the presence of FL and IL-15 showed a rapid decrease in CD14 expression after day 5, which reached levels of zero by day 20. Approximately 60% of the CD56(+) derived from the UCB/ACF or the UCB/CD14(+) cells coexpressed CD14 by day 5. Taken together, our data support the role of CD14(+) myeloid-like cells within UCB as a novel progenitor for lymphoid NK cells.
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PMID:A novel myeloid-like NK cell progenitor in human umbilical cord blood. 1250 32

4-1BB ligand (4-1BBL), a member of the tumor necrosis factor (TNF) superfamily, interacts with 4-1BB (CDw137) expressed on activated T cells and delivers a costimulatory signal for T cell activation and growth. Various studies have demonstrated a role for murine 4-1BB in immune function, but relatively few investigations of human 4-1BB have been conducted. Here we report on the construction of a recombinant E1/E3-deleted adenovirus encoding human 4-1BBL (Ad4-1BBL) and its stimulation of antitumor immunity. Ad4-1BBL was able to efficiently infect several human adenocarcinoma cell lines and induce 4-1BBL expression on the cell surface within 24 h, this enhancing the antitumor activity not only of lymphokine-activated killer cells with a T cell phenotype (T-LAK) but also naive peripheral blood mononuclear cells (PBMC). This antitumor activity with T-LAK cells was further enhanced by addition of bispecific antibody (BsAb; anti-MUC1xanti-CD3). Cocultivation of Ad4-1BBL-infected tumor cells with either T-LAK cells or PBMC resulted in significant elevation of interferon-gamma (IFN-gamma), interleukin-2 (IL-2), and granulocyte-macrophage colony-stimulating factor (GM-CSF) production. Furthermore, remarkable tumor growth inhibition was observed in cholangiocarcinoma-grafted severe combined immunodeficient (SCID) mice to which Ad4-1BBL and T-LAK cells were administered when tumor size exceeded 5 mm in diameter. These results provide strong evidence in support of the efficacy of adenovirally delivered 4-1BBL for genetic immunotherapy of cancer.
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PMID:A novel adenovirus expressing human 4-1BB ligand enhances antitumor immunity. 1259 73

We investigated the efficacy of Mo17-1A to improve important immunological parameters in vivo and in vitro in colorectal cancer (CRC) patients receiving no second-line treatment. Eighteen CRC patients stage Dukes' C were treated postoperatively with 5 doses of Mo17-1A. Peripheral blood mononuclear cells (PBMC) were analyzed for proliferative responses and cytolytic activity. Serum levels of cytokines were determined during treatment. Enhancement in the proliferative activity of patients' T cells, improvement in their lymphocytes' killing ability of natural killer (NK) and lymphokine-activated killer (LAK) sensitive tumor targets, and an in vivo increase in serum levels of interleukin (IL)-2, IL-12, IL-15, interferon (IFN)-gamma and granulocyte-macrophage colony-stimulating factor (GM-CSF) were noted. We conclude that treatment of CRC patients with Mo17-1A partially restores deficient cellular immune responses and the secretion of cytokines with immuno-enhancing properties. The development of novel immunotherapeutic protocols using combinations of Mo17-1A with stimuli that enhance the lytic capacity of effector cells (e.g. cytokines), may improve clinical responses in these types of patients.
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PMID:Immune changes in patients with colorectal cancer treated by adjuvant therapy with monoclonal antibody 17-1A: a pilot study. 1296 68

Release of granulocyte macrophage-colony-stimulating factor (GM-CSF) from T cells is important in the differentiation, maturation, and survival of inflammatory cells. Here the induction of GM-CSF expression from T cells was dependent on transcription and translation and was prevented by dexamethasone. In primary human CD3(+) T cells, up to 3.3 kb of human GM-CSF promoter was strongly activated by PMA + PHA. Mutations in either the -85/-76 nuclear factor (NF)-kappaB site or the activator protein-1 region in the -54/-31 conserved lymphokine element 0 (CLE0) site substantially reduced promoter activity. Both GM-CSF promoter and NF-kappaB-dependent constructs were unresponsive to dexamethasone whereas the release of GM-CSF was potently repressed. Analysis of GM-CSF mRNA and protein expression at various time points and the effect of adding dexamethasone after the stimulus revealed the existence of potent mechanisms of inhibition acting at a translational level. The expression of tristetraproline and HuR, proteins that bind the AU-rich element in the GM-CSF 3'-untranslated region was unaffected by dexamethasone and overall AU-rich element binding activity was unaltered. Taken together our data support an important role for the NF-kappaB and CLE0 sites in the transcriptional control of GM-CSF expression in primary human T cells and suggest that post-transcriptional/translational mechanisms are key mediators of glucocorticoid-dependent repression.
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PMID:Glucocorticoid inhibition of granulocyte macrophage-colony-stimulating factor from T cells is independent of control by nuclear factor-kappaB and conserved lymphokine element 0. 1452 27

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) reporter constructs containing up to 3.3 kb of upstream promoter sequence were transiently transfected into both Jurkat and HUT78 human T-cell lines. In Jurkat cells, stimulation with phorbol 12-myristate 13-acetate (PMA) plus phytohemaglutinin (PHA) produced robust increases in reporter activity, whereas HUT78 cells showed low levels of reporter induction attributable to constitutive nuclear factor (NF)-kappaB activity. Following mutation of either the proximal NF-kappaB site (-85/-76) or the activator protein1 (AP-1) motif within the conserved lymphokine element 0 (CLE0) site (-54/-31), reporter activity was markedly reduced in both cell lines. Despite this dependence on NF-kappaB and CLE0/AP-1, GM-CSF reporter activity was unaffected by dexamethasone in either cell line. Similarly, an NF-kappaB-dependent reporter was also not repressed by dexamethasone, yet GM-CSF release from HUT78 T cells was inhibited. These data therefore confirm a critical role for both NF-kappaB and CLE0 sites in GM-CSF promoter activation and indicate that NF-kappaB may not mediate glucocorticoid-dependent repression of GM-CSF in these cells.
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PMID:Nuclear factor-kappaB does not mediate the inhibitory effects of dexamethasone on granulocyte-macrophage colony-stimulating factor expression. 1505 80


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