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)

In neutrophils, four different granules are defined, i.e. azurophil, specific, gelatinase and secretary vesicles. In these granules many neutrophil-specific constituents are identified. Some of these constituents have already been cloned and their gene expressions studied. In such constituents, alkaline phosphatase (ALP) and defensin are well known, although their functions are not yet fully clarified. ALP is present in secretary vesicles and has important roles in the diagnosis of some myeloid disorders. On the other hand, defensin is the most abundant functional peptide of neutrophils and is present in azurophillic granules. Which are subdivided into defensin-rich and defensin-poor granules. This review describes the expression of ALP and the defensin gene in normal and leukemic cells and the effect on these genes of myeloid growth factors, such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and interleukin 3.
Leuk Lymphoma 1999 Jan
PMID:Alkaline phosphatase, defensin gene expression and effect of myeloid cell growth factors in normal and leukemic cells. 1003 21

Myeloperoxidase (MPO) is present in azurophilic granules which appear in the promyelocyte stage of differentiation, and is the most common functional protein of myeloid cells. With progress in molecular biology, the expression and regulation of MPO have been clarified in normal myeloid and leukemic cells, not only by enzymatical activity but at the gene level MPO expression is affected by the differentiation of myeloid cells, and has been suggested to be regulated by myeloid cell growth factors, such as granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor and interleukin-3. In the past decade the signal transduction from their receptors has been clarified. This review describes the expression and regulation of the MPO gene in myeloid cells including myeloid disorders, such as myeloid leukemia or myelodysplastic syndromes, The effects on MPO by myeloid growth factors and signal transduction from their receptors are also presented.
Leuk Lymphoma 1999 Jan
PMID:Myeloperoxidase gene expression and regulation by myeloid cell growth factors in normal and leukemic cells. 1003 23

The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) on the number of granulocytes in peripheral blood and myeloid cells in the bone marrow were studied in seven patients with chronic lymphocytic leukemia (CLL). The neutrophil count in the peripheral blood rose by a median of 193% (range 142-980%), p = 0.02, and the increase persisted for more than 2 weeks after discontinuation of the treatment. The percentage of myeloid cells in bone marrow increased by 166% (range--57-1800%). In neutropenic CLL patients with recurrent infections GM-CSF treatment may constitute a new treatment modality.
Leuk Lymphoma 1999 Jan
PMID:GM-CSF treatment in patients with B-chronic lymphocytic leukemia. 1003 35

We converted a model, syngeneic, nonimmunogenic tumor antigen into a vaccine by fusing it with a proinflammatory chemokine. Two chemokines, interferon inducible protein 10 and monocyte chemotactic protein 3, were fused to lymphoma Ig variable regions (sFv). The sFv-chemokine fusion proteins elicited chemotactic responses in vitro and induced inflammatory responses in vivo. Furthermore, in two independent models, vaccination with DNA constructs encoding the corresponding fusions generated superior protection against a large tumor challenge (20 times the minimum lethal dose), as compared with the best available protein vaccines. Immunity was not elicited by controls, including fusions with irrelevant sFv; fusions with a truncated chemokine that lacked receptor binding and chemotactic activity; mixtures of free chemokine and sFv proteins; or naked DNA plasmid vaccines encoding unlinked sFv and chemokine. The requirement for linkage of conformationally intact sFv and functionally active chemokine strongly suggested that the mechanism underlying these effects was the novel targeting of antigen presenting cells (APC) for chemokine receptor-mediated uptake of antigen, rather than the simple recruitment of APC to tumor by the chemokine. Finally, in addition to superior potency, these fusions were distinguished from lymphoma Ig fusions with granulocyte-macrophage colony-stimulating factor or other cytokines by their induction of critical effector T cells.
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PMID:Genetic fusion of chemokines to a self tumor antigen induces protective, T-cell dependent antitumor immunity. 1009 84

The effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on B lymphocytes from persistent lymphocytosis (PL) cattle and lymphoma cells induced by bovine leukemia virus (BLV) was studied in vitro. Flow cytometric analysis showed that high levels of receptors to GM-CSF were expressed on these cell types. Proliferation of these B cells was induced in response to bovine GM-CSF. In tumor cell lines, the rate of cell proliferation was correlated with expression of GM-CSF receptors. A monoclonal antibody to GM-CSF inhibited lymphocyte proliferation and blocked the GM-CSF binding of lymphocytes. Cells expressing GM-CSF receptor were Ig positive and both CD5 and CD11 positive (B-1a cell). These results suggest that an abnormal expression of GM-CSF receptors on B lymphocytes from PL and lymphoma cells induced by BLV plays important roles in the PL and proliferation of lymphoma.
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PMID:Expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor on B-1a cell from persistent lymphocytosis (PL) cows and lymphoma cell induced by bovine leukemia virus. 1023 51

Murine monoclonal antibody (MoAb) Lym-1 is an IgG2a able to bind HLA-DR variants on malignant B cells and suitable for serotherapeutic approaches in B-lymphoma patients. We have previously shown that Lym-1 can synergize with granulocyte-macrophage colony-stimulating factor (GM-CSF) to trigger neutrophil cytolysis towards Raji cells used as a model of B-lymphoma targets. Here we provide evidence for the intervention of certain neutrophil receptors or surface molecules in this model of cell-mediated lysis. The lysis was completely inhibited by the anti-FcgammaRII MoAb IV.3 and unaffected by the anti-FcgammaRIII MoAb 3G8. This suggests that neutrophil cytolysis involves FcgammaRII without cooperation of this receptor with FcgammaRIII. Moreover, the lysis was inhibited by an anti-CD18 MoAb (MEM48) and by a MoAb specific for carcinoembryonic antigen (CEA)-like and glycophosphatidyl inositol (GPI)-linked glycoproteins (CD66b). Using an immunofluorescence staining procedure, cross-linking of CD66b induced the redistribution of CD11b on neutrophils with distinct areas of CD11b clustering via a process susceptible of inhibition by D-mannose. This is consistent with the ability of CD11b-CD18 and CD66b to undergo lectin-like physical interactions on the neutrophil surface. Such a type of interaction is presumably instrumental for neutrophil cytolytic activity in that the lysis was inhibited by D-mannose and enhanced by the MoAb VIM-12, which mimics the cooperation between CD11b and GPI-anchored molecules by specifically interacting with CD11b lectin-like sites. Therefore, the present results prove the absolute requirement for FcgammaRII in neutrophil GM-CSF/Lym-1-mediated cytolysis and, on the other hand, define the crucial role of CD66b and CD11b/CD18 in the expression of the cell lytic potential.
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PMID:Monoclonal Lym-1 antibody-dependent cytolysis by neutrophils exposed to granulocyte-macrophage colony-stimulating factor: intervention of FcgammaRII (CD32), CD11b-CD18 integrins, and CD66b glycoproteins. 1023 3

The mononuclear phagocyte system consists of peripheral blood monocytes and tissue macrophages that collectively play a major role in host immunity. Far from existing solely as phagocytic scavengers of cell debris and foreign matter, monocytes are highly active and responsive to inflammatory and immunological signals that activate their microbicidal and tumoricidal functions. Cytokines that are secreted as an integral component of the innate immune response such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and -IFN may directly activate the functions of the monocyte system. A key mediator of the effector functions of monocytes is tumour necrosis factor (TNF) which transduces its signals upon binding to specific transmembrane receptors. TNF is highly cytotoxic to micro-organisms and susceptible malignant cells and in most cases delivers its cytotoxic signal to tumour cells by highly regulated mechanisms of programmed cell death or apoptosis. We believe that the numerous functions of the monocyte system may be harnessed for therapeutic gain both in the context of microbiological infection and malignant disease. In this review, the mechanisms by which secreted and monocyte cell-membrane-associated TNF induce apoptosis will be discussed. In addition, the cell-associated and secretory immunological mechanisms employed by monocytes in host defence will be discussed in the context of the their ability to combat infection and neoplasia.
Leuk Lymphoma 1999 Jun
PMID:The potential for monocyte-mediated immunotherapy during infection and malignancy. Part I: apoptosis induction and cytotoxic mechanisms. 1035 Mar 28

The monocyte system exhibits a range of immunological mechanisms that may be harnessed for therapeutic effect against infection and malignancy. The advent of novel therapies aimed at treating infection and malignancy is complemented by a resurgence of clinical interest in immunotherapeutic programmes to treat diseases by modification or direct augmentation of host immunity. Cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and IFN-gamma modulate the function of monocytes and have been used to experimentally probe the immunotherapeutic potential of monocytes against micro-organisms and malignancy. However, monocytes rarely act alone but communicate with other leukocytes involved in cell-mediated immunity. In particular monocytes cooperate with the T-helper (Th1 and Th2) sub-populations of peripheral lymphocytes. Moreover, sub-populations of monocytes, as identified by the co-expression of membrane-associated CD14 and CD16, have been shown to exist. At the preclinical level, this provides a unique opportunity to explore the effect of immunotherapeutic strategies on the function of monocyte sub-populations against infectious or malignant challenge and may allow immunotherapeutic strategies to be targeted towards specific monocyte sub-populations. Preclinical and clinical studies in human subjects suggest that GM-CSF and other cytokines such as IFN-gamma are the most promising biological response modifiers for augmenting monocyte-mediated immunity. In this review, the immunotherapeutic potential of the monocyte system will be discussed in the context of combating microbial and malignant disease.
Leuk Lymphoma 1999 Jul
PMID:The potential for monocyte-mediated immunotherapy during infection and malignancy--Part II: in vivo activation by exogenous cytokines and clinical applications. 1043 59

A fusion protein containing a B cell lymphoma idiotype (Id) and granulocyte-macrophage colony-stimulating factor (GM-CSF) is a potent stimulator of tumor immunity. In three different tumor models we show that immunization with autologous lymphoma cells that have been engineered to express the Id in the context of GM-CSF is much more effective than immunization with an equivalent dose of the purified protein. The lymphoma Id could be modified by introducing the GM-CSF gene into the immunoglobulin (Ig) heavy chain locus via gene targeting. This approach circumvents the isolation of the rearranged immunoglobulin variable genes from the tumor and the preparation of tumor-specific vector constructs. The low production of Id/GM-CSF fusion proteins by transfected cells, which is a major obstacle in the use of purified fusion proteins for immunotherapy, is due to the presence of the cytokine gene in the immunoglobulin locus. Low production, however, is not limiting in the cell-based setting, because upon in vivo administration of the modified autologous cells, even minute expression levels are sufficient to induce tumor immunity.
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PMID:Induction of tumor immunity by autologous B lymphoma cells expressing a genetically engineered idiotype. 1050 1

Natural killer-like T lymphocytes termed cytokine-induced killer (CIK) cells have been shown to eradicate established tumours in a severe combined immune deficient (SCID) mouse/human lymphoma model. Recently, we demonstrated that CIK cells transfected with cytokine genes possess an improved proliferation rate and a significantly higher cytotoxic activity as compared to non-transfected cells. Here, in a phase I clinical protocol, autologous CIK cells were generated from peripheral blood obtained by leukapheresis in patients with metastatic renal cell carcinoma, colorectal carcinoma and lymphoma. CIK cells were transfected with a plasmid containing the interleukin-2 (IL-2) gene via electroporation. Transfected cells generated IL-2 in the range of 330-1800 pg 10(-6) cells 24 h(-1) with a mean of 836 pg 10(-6) cells 24 h(-1). Ten patients received 1-5 intravenous infusions of IL-2-transfected CIK cells; five infusions with transfected CIK cells were given. In addition, the same patients received five infusions with untransfected CIK cells for control reasons. In three patients, WHO grade 2 fever was observed. Based on polymerase chain reaction of peripheral blood transfected cells could be detected for up to 2 weeks after infusion. There was a significant increase in serum levels of interferon gamma (IFN-gamma), granulocyte-macrophage colony-stimulating factor (GM-CSF) and transforming growth factor beta (TGF-beta) during treatment. Interestingly, there was also an increase in CD3+ lymphocytes in the blood of patients during therapy. In accordance, a partial increase in cytotoxic activity in peripheral blood lymphocytes (PBLs) was documented when patient samples before and after therapy were compared. Concerning clinical outcome, six patients remained in progressive disease, three patients showed no change by treatment, and one patient with lymphoma developed a complete response. In conclusion, we were able to demonstrate that CIK cells transfected with the IL-2 gene can be administered without major side-effects and are promising for future therapeutic trials.
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PMID:Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. 1057 58


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