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)

Mast cells (MCs) originate from multipotent hematopoietic progenitor cells. However, MCs in various organs are heterogenous in terms of mediator or receptor expression and response to diverse stimuli. We characterized the phenotype and functional properties of human renal mast cells (HRMCs). Tissue was obtained from 17 patients suffering from renal tumors (transitional cell carcinoma, n = 4; renal cell carcinoma, n = 13). HRMCs were isolated by collagenase digestion. Double staining with toluidine blue and immunofluorescence using monoclonal antibodies (mAbs) revealed expression of stem cell factor (SCF)-receptor (c-kit/CD117), CD9, CD29, CD33, CD43, CD44, CD54, and CD63 on HRMCs. In contrast, HRMCs were not recognized by mAbs to CD2, CD3, CD4, CD11b, CD14, CD15, CD16, CDw17, CD19, or CD23. HRMCs were also negative for CD116 (granulocyte-macrophage colony-stimulating factor [GM-CSF] receptor alpha), CD123 (interleukin [IL]-3Ralpha), CD121a (IL-1R type I), CD122 (IL-2Rbeta), and CD127 (IL-7R) and were also found to lack C5aR (CD88). Ligand-induced activation of HRMCs through immunoglobulin (Ig)E-R or SCF-R (c-kit) resulted in histamine secretion (control: <10%; alphaIgE, 1 microg/mL: 50.12 +/-5.18%; rhSCF, 100 ng/mL: 29.24 +/- 22.39), whereas recombinant C5a, erythropoietin (EPO), IL-1 through 10, and GM-CSF exerted no effects. As determined by in situ staining, HRMCs contained tryptase, but only low or undetectable amounts of chymase. Electron microscopy confirmed the presence of MCs in renal tissues and revealed a scroll-rich granule population in HRMCs. Together, HRMCs are tryptase+, C5aR- mast cells exhibiting phenotypic and functional properties similar to those of lung MCs.
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PMID:Phenotypic and functional characterization of mast cells derived from renal tumor tissues. 947 5

Current data support the notion that the thymus is seeded by a yet uncommitted progenitor cell able to generate T cells, B cells, natural killer (NK) cells, and dendritic cells (DCs). We assess in this report the developmental relationship of DCs and NK cells derived from a small subset of CD34(+) human postnatal thymocytes that, like the earliest precursors in the fetal thymus, display low CD33 surface expression. Culture of these isolated CD34(+) CD33(lo) thymic progenitors with a mixture of cytokines, including interleukin-7 (IL-7), IL-1alpha, IL-6, granulocyte-macrophage colony-stimulating factor, and stem cell factor, results in predominant generation of DCs. However, the addition of IL-2 to the cytokine mixture leads to the simultaneous development of DCs and NK cells. Both developmental pathways progress through a transient population of CD34(+)CD44(bright) CD5(lo/-)CD33(+) large-sized cells, distinct from small-sized T-lineage precursors, that contain bipotential NK/DC progenitors. These data provide evidence of linked pathways of NK cell and DC development from intrathymic precursors and suggest that NK cells and DCs branch off the T lineage through a common intermediate progenitor.
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PMID:Identification of a common developmental pathway for thymic natural killer cells and dendritic cells. 953 86

The CD14-dependent and -independent dendritic cell (DC) pathways are instituted simultaneously when CD34(+) progenitor cells are treated with granulocyte-macrophage colony-stimulating factor (GM-CSF)/tumor necrosis factor (TNF) +/- stem cell factor (SCF) (GTS). If TNF activity is neutralized within 48 hours of cytokine exposure, DC development is halted and myelogranulocytic hematopoiesis takes place. In this study, we show that disruption of TNF activity at a later time point produced a distinct alteration within the DC system. Instead of downregulating DC development, treatment of GTS cultures with antibodies to TNF (anti-TNF) on day 3 provoked the selective expansion of the CD14-dependent (monocyte) DC pathway from progenitor cell populations lacking CD14 and CD1a. After an initial decrease in proliferation, anti-TNF produced a rebound in cell growth that yielded intermediate myeloid progenitors exhibiting CD14-dependent DC differentiation potential and CD14(+)CD1a+ DC precursors. Cultures enriched in CD14-dependent DCs were more potent stimulators of a mixed leukocyte reaction, compared with control GTS cultures containing both types of DCs. The intermediate progenitors expanded in the presence of anti-TNF were CD115(+)CD33(+)DR+, long-lived, and displayed clonogenic potential in methylcellulose. When exposed to the appropriate cytokine combinations, these cells yielded granulocytes, monocytes, and CD14-dependent DCs. Antigen-presenting function was acquired only when DC maturation was induced from these myelodendritic progenitors with GM-CSF + interleukin-4 or GTS. These studies show a novel mechanism by which TNF regulates the DC system, as well as providing a strategy for the amplification of the CD14-dependent DC pathway from immature progenitors. Although TNF is required to ensure the institution of DC hematopoiesis from CD34(+) progenitor cells, its activity on a later progenitor appears to limit the development of CD14-dependent DCs.
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PMID:Neutralization of tumor necrosis factor activity shortly after the onset of dendritic cell hematopoiesis reveals a novel mechanism for the selective expansion of the CD14-dependent dendritic cell pathway. 968 Mar 40

Dendritic cells (DC) can be generated by culture of adherent peripheral blood (PB) cells in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-4 (IL-4). There is controversy as to whether these DC arise from proliferating precursors or simply from differentiation of monocytes. DC were generated from myeloid-enriched PB non-T cells or sorted monocytes. DC generated from either population functioned as potent antigen-presenting cells. Uptake of [3H]-thymidine was observed in DC cultured from myeloid-enriched non-T cells. Addition of lipopolysaccharide or tumor necrosis factor-alpha led to maturation of the DC, but did not inhibit proliferation. Ki67(+) cells were observed in cytospins of these DC, and by double staining were CD3(-)CD19(-)CD11c-CD40(-) and myeloperoxidase+, suggesting that they were myeloid progenitor cells. Analysis of the starting population by flow cytometry demonstrated small numbers of CD34(+)CD33(-)CD14(-) progenitor cells, and numerous granulocyte-macrophage colony-forming units were generated in standard assays. Thus, production of DC in vitro from adherent PB cells also enriches for progenitor cells that are capable of proliferation after exposure to GM-CSF. Of clinical importance, the yield of DC derived in the presence of GM-CSF and IL-4 cannot be expanded beyond the number of starting monocytes.
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PMID:Proliferation in monocyte-derived dendritic cell cultures is caused by progenitor cells capable of myeloid differentiation. 971 87

The application of ex vivo expansion to cell products pharmacologically purged in vitro may provide sufficient numbers of cells for rapid engraftment in a product with reduced tumor burden. To pursue this possibility we evaluated the effect of 4-hydroperoxycyclophosphamide (4-HC) treatment on granulocyte colony-stimulating factor-mobilized peripheral blood stem cells (G-PBSC) and their subsequent expansion potential. A small number of G-PBSC CD34+ cells are resistant to 4-HC and are phenotypically and functionally immature. 4-HC-resistant G-PBSC cells are CD34+ bright, CD38+/-, DR(lo), CD13(lo), CD33-, CD71-, and rhodamine dull. In six experiments, treating G-PBSC with 60 microg/mL of 4-HC at 37 degrees C for 30 minutes reduced the number of colony-forming units (CFUs) per 5000 CD34+ cells by 96.3% (from 1333 +/- 137 to 46.5 +/- 11). This purging also reduced the frequency of 5-week long-term culture initiating cells (LTC-ICs) from 1/39 (range 1/27 to 1/62) to <1/1680 (range 1/1180 to 1/2420). Ex vivo expansion cultures were used to compare the proliferative potential of treated and untreated CD34+ cells. These cells were cultured with either the HS-5 stromal cell line serum-deprived conditioned media supplemented with 10 ng/mL kit ligand (HS-5CM/KL) or a recombinant growth factor mix (GFmix) containing 10 ng/mL each of interleukin (IL)-1, IL-3, IL-6, KL, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and 3 U/mL of erythropoietin. Culturing untreated CD34+ G-PBSC with 10% HS-5CM/KL increased total nucleated cells by 460-fold after 15 days. Progenitors, which were measured as CFUs, also increased by 47-fold over the same period. More significantly, culturing the 4-HC-treated CD34+ cells with HS-5/KL increased CFUs 98-fold and the nucleated cells increased 4573-fold. The absolute number of CFUs present after expansion of the 4-HC-resistant cells with HS-5CM/KL was threefold higher than that detected before purging and significantly higher than that obtained with GFmix. These data indicate that G-PBSC contain a very immature pool of cells not detectable using the 5-week LTC-IC assay, but have extremely high proliferative potential. Additionally, pharmacological purging of G-PBSC greatly reduces mature cells while retaining an immature population. Also significant is the finding that supernatant from the HS-5 bone marrow stromal cell line plus KL can fully regenerate progenitors from the 4-HC-resistant CD34+ G-PBSC.
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PMID:Ex vivo expansion of immature 4-hydroperoxycyclophosphamide-resistant progenitor cells from G-CSF-mobilized peripheral blood. 976 8

We have previously reported that vitamin K2 (VK2) has a potent apoptosis inducing activity toward various types of primary cultured leukemia cells including acute myelogenous leukemia arising from myelodysplastic syndromes (MDS). We established a novel cell line, designated MDS-KZ, from a patient with MDS in blastic transformation, and further investigated the effects of VK2 using this novel cell line. MDS-KZ shows complex chromosomal anomaly including -4, 5q-, -7, 13q+, 20q-, consistent with that seen in the original patient. Culture of MDS-KZ cells in RPMI1640 medium containing 10% FBS lead to steady but very slow proliferation with a doubling time of 14 days. However, the cellular growth rate was significantly accelerated in the presence of various growth factors such as granulocyte colony-stimulating factor, stem cell factor, granulocyte-macrophage colony-stimulating factor, interleukin-3, and thrombopoietin. Most of the cultured cells show the morphological features of myeloblasts. They are positive for CD7, CD33, CD34, CD45, CD117, and HLA-DR. However, about 10% of the cells are more mature metamyelocytes and neutrophils with various dysplastic characteristics such as pseudo-Pelger nuclear anomaly and hypersegmentation, suggesting a potential for differentiation in this cell line. As previously reported for cultured primary leukemia cells, exposure to VK2, but not to VK1, resulted in induction of apoptosis of MDS-KZ cells in a dose-dependent manner (IC50: 5 microM). In addition, VK2 treatment induced down-regulation of BCL-2 and up-regulation of BAX protein expression with concomitant activation of caspase-3 (CPP32). A tetrapeptide functioning as antagonist of caspase-3, Ac-DEVD-H, suppressed the VK2-induced inhibition of cell growth, suggesting that caspase-3 is, at least in part, involved in VK2-induced apoptosis. These observations suggest that the MDS-KZ cell line can serve as a model for the study of the molecular mechanisms of VK2-induced apoptosis.
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PMID:Vitamin K2 induces apoptosis of a novel cell line established from a patient with myelodysplastic syndrome in blastic transformation. 1048 91

Myelokathexis is a congenital disorder that causes severe chronic leukopenia and neutropenia. Characteristic findings include degenerative changes and hypersegmentation of mature neutrophils and hyperplasia of bone marrow myeloid cells. The associated neutropenia can be partially corrected by treatment with granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF). These features led us to propose that accelerated apoptosis of neutrophil precursors might account for the neutropenic phenotype. Blood and bone marrow aspirates were obtained from 4 patients (2 unrelated families) with myelokathexis before G-CSF therapy and from 2 of the affected persons after G-CSF therapy (1 microg/kg per day subcutaneously for 3 weeks). Bone marrow was fractionated using immunomagnetic bead cell sorting into CD34(+), CD33(+)/CD34(-), and CD15(+)/CD34(-)/CD33(- )cell populations. Examination of these cells by flow cytometry and electron microscopy revealed abundant apoptosis in the CD15(+) neutrophil precursor population, characterized by enhanced annexin-V binding, extensive membrane blebbing, condensation of heterochromatin, and cell fragmentation. Colony-forming assays demonstrated significant reduction in a proportion of bone marrow myeloid-committed progenitor cells. Immunohistochemical analysis revealed a selective decrease in bcl-x, but not bcl-2, expression in the CD15(+)/CD34(-)/CD33(-)cell population compared with similar subpopulations of control bone marrow-derived myeloid precursors. After G-CSF therapy, apoptotic features of patients' bone marrow cells were substantially reduced, and the absolute neutrophil counts (ANC) and expression of bcl-x in CD15(+)/CD34(-)/CD33(-)cells increased. The authors concluded that myelokathexis is a disease characterized by the accelerated apoptosis of granulocytes and the depressed expression of bcl-x in bone marrow-derived granulocyte precursor cells. These abnormalities are partially corrected by the in vivo administration of G-CSF. (Blood. 2000;95:320-327)
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PMID:Myelokathexis, a congenital disorder of severe neutropenia characterized by accelerated apoptosis and defective expression of bcl-x in neutrophil precursors. 1060 19

P75/AIRM1 is a recently identified surface molecule that belongs to the sialoadhesin family and displays homology with the myeloid cell antigen CD33. In lymphoid cells, p75/AIRM1 is confined to natural killer cells and mediates inhibition of their cytolytic activity. In this study, we show that p75/AIRM1 is also expressed by cells of the myelomonocytic cell lineage, in which it appears at a later stage as compared with CD33. In vitro proliferation and differentiation of cord blood-derived CD34(+) cells (induced by stem cell factor and granulocyte-macrophage colony-stimulating factor) were consistently inhibited by the addition of anti-p75/AIRM1 mAb. Engagement of CD33 led to inhibition in some experiments. A sharp decrease of cell proliferation/survival was detected in all three p75/AIRM1+ chronic myeloid leukemias analyzed when cultured in the presence of either anti-p75/AIRM1 or anti-CD33 mAbs. Thus, the present study suggests that p75/AIRM1 and CD33 may play a regulatory role in normal myelopoiesis and may be viewed as suitable target molecules to counteract the proliferation/survival of chronic myeloid leukemias.
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PMID:Engagement of p75/AIRM1 or CD33 inhibits the proliferation of normal or leukemic myeloid cells. 1061 43

Conventional chemotherapeutic treatments of acute leukemias are often associated with life-threatening toxic effects due to a lack of specificity for hematopoietic cells. Monoclonal antibodies and fusion proteins that target antigens on leukemic blasts are being explored for their antileukemic effects and as a means of delivering chemotherapy or radiation directly to malignant cells. This approach might be safer and more effective than current non-specific chemotherapeutic agents. The cell surface antigens CD33 and CD45 are attractive targets. Although CD33 is expressed on acute myelocytic leukemic blast cells from about 90% of patients, normal hematopoietic stem cells lack this antigen, as do essentially all non-hematopoietic tissues. Anti-CD33 antibodies have been engineered to selectively target malignant myeloid and immature normal cells while sparing normal stem cells. Recently, anti-CD33 antibodies have also been used to deliver radiation or a cytotoxic agent directly to leukemic cells. The strategy for using CD45 as a target differs from CD33 in that it is expressed not only by the vast majority of leukemias, but also by normal stem cells. Therefore, 131I-labeled anti-CD45 antibody has been used in combination with conventional preparative regimens for patients receiving marrow transplantation for acute leukemia. Because the receptor for granulocyte-macrophage colony-stimulating factor is expressed by most myeloid leukemias, fusion proteins consisting of granulocyte-macrophage colony-stimulating factor ligand associated with diphtheria toxin have been proposed as a means of delivering a toxic agent directly to leukemic cells. Both unconjugated and conjugated antibodies show significant promise in the treatment of acute myelocytic leukemia.
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PMID:Clinical studies of new "biologic" approaches to therapy of acute myeloid leukemia with monoclonal antibodies and immunoconjugates. 1068 26

Although CD33 represents an important marker of myeloid cell differentiation, its function remains poorly defined. In view of its homology with p75/AIRM1, a recently identified surface molecule which exerts a potent inhibition on NK cell function, we re-evaluated the effect of CD33 engagement in defined myeloid cell functions. Addition of anti-CD33 mAb to cultures of CD14+ monocytes supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-4 and TNF-alpha, prevented the generation of dendritic cells. In these cultured cells, engagement of CD33 resulted in an increased surface binding of annexin-V, followed by cell death. Mature dendritic cells were resistant to the CD33-mediated effect. Also in CD34+ precursors, cultured in the presence of flt3-ligand, c-Kit-ligand, GM-CSF, IL-4 and TNF-alpha, addition of anti-CD33 mAb prevented the recovery of mature dendritic cells. These data suggest a regulatory role of CD33 in the myeloid cell maturation and may offer a tool to interfere with the monocyte/macrophage cell function as well as with the development of dendritic cells.
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PMID:Engagement of CD33 surface molecules prevents the generation of dendritic cells from both monocytes and CD34+ myeloid precursors. 1074 98


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