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)

In this study, we analyzed the expression and function of the lymphocyte surface lectin NKRP1A on peripheral blood monocytes (Mo) or Mo and dendritic cells (DC) derived from thymic and bone marrow precursors. De novo expression of NKRP1A and CD14 molecules was detected upon culture of CD2- CD3- CD14- CD16- CD1a- NKRP1A- immature thymic precursors for 7 days in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF). Under these culture conditions, by day 21, a fraction of cells had lost CD14 and acquired both CD80 (B7.1) and CD86 (B7.2) molecules. These cells displayed a DC-like morphology and were surface NKRP1A positive. CD34+ NKRP1A- CD14- precursors, isolated from bone marrow and cultured in the presence of GM-CSF, also expressed both NKRP1A and CD14: these antigens were newly expressed on about one third of cells which had lost the CD34 precursor marker. In addition, NKRP1A was constitutively present on resting CD14+ peripheral blood Mo. When these cells were cultured in the presence of GM-CSF, the resulting DC population retained the expression of NKRP1A and acquired CD80, while they lost the CD14 antigen. Functional analysis revealed that the engagement of NKRP1A molecule leads to a strong intracellular calcium ([Ca2+]i) increase both in resting peripheral blood Mo and in vitro-derived DC. [Ca2+]i increase was mainly due to extracellular calcium influx, as it was completely abrogated by the addition of EGTA. More importantly, the engagement of the NKRP1A molecule induced interleukin (IL)-1 beta and IL-12 production by resting Mo and DC, respectively. Altogether these data indicate that NKRP1A lectin is present at the surface of Mo and DC and may play a relevant role in the activation and function of both cell types.
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PMID:Expression and function of NKRP1A molecule on human monocytes and dendritic cells. 939 25

An animal model of chronic myeloid leukemia (CML) will help characterize leukemic and normal stem cells and also help evaluate experimental therapies in this disease. We have established a model of CML in the NOD/SCID mouse. Infusion of > or = 4 x 10(7) chronic-phase CML peripheral blood cells results in engraftment levels of > or = 1% in the bone marrow (BM) of 84% of mice. Engraftment of the spleen was seen in 60% of mice with BM engraftment. Intraperitoneal injection of recombinant stem cell factor produced a higher level of leukemic engraftment without increasing Philadelphia-negative engraftment. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor did not increase the level of leukemic or residual normal engraftment. Assessment of differential engraftment of normal and leukemic cells by fluorescence in situ hybridization analysis with bcr and abl probes showed that a median of 35% (range, 5% to 91%) of engrafted cells present in the murine BM were leukemic. BM engraftment was multilineage with myeloid, B-cell, and T-cell engraftment, whereas T cells were the predominant cell type in the spleen. BM morphology showed evidence of eosinophilia and increased megakaryocytes. We also assessed the ability of selected CD34+ CML blood cells to engraft NOD/SCID mice and showed engraftment with cell doses of 7 to 10 x 10(6) cells. CD34- cells failed to engraft at cell doses of 1.2 to 5 x 10(7). CD34+ cells produced myeloid and B-cell engraftment with high levels of CD34+ cells detected. Thus, normal and leukemic stem cells are present in CD34+ blood cells from CML patients at diagnosis and lead to development of the typical features of CML in murine BM. This model is suitable to evaluate therapy in CML.
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PMID:Establishment of a reproducible model of chronic-phase chronic myeloid leukemia in NOD/SCID mice using blood-derived mononuclear or CD34+ cells. 942 19

We recently established an acute promyelocytic leukemia (APL) cell line (HT93) that has the capacity to differentiate into neutrophils and eosinophils in response to all-trans retinoic acid (ATRA) and human hematopoietic cytokines. The cells had a myeloblastic morphology, were positive for surface CD33, CD34, and CD56, and showed the following karyotypes: 46, XY, t(1;12)(q25;p13), 2q+, t(4;6)(q12;q13), and t(15;17)(q22;q11). When the cells were cultured with ATRA, they showed nuclear segmentation and developed secondary granules consisting in part of neutrophils and eosinophils. In the presence of ATRA and granulocyte colony-stimulating factor (G-CSF), the cells showed polymorphonuclear neutrophil differentiation accompanied by expression of surface CD11b, CD15, CD10, positive activity for neutrophil alkaline phosphatase (NAP), and NAP mRNA expression. In cultures with ATRA and granulocyte-macrophage colony-stimulating factor (GM-CSF), IL (interleukin)-3, or IL-5, HT93 showed remarkable eosinophil maturation at day 8 as determined by luxol fast blue staining, in addition to expression of eosinophil peroxidase and major basic protein. These results indicate that HT93 is an APL cell line with the ability to differentiate into neutrophils and eosinophils, and that these lineages are dependent on the CSF added. HT 93 should prove to be a useful model in analyzing the effects of hematopoietic cytokines on proliferation, differentiation, and maturation of hematopoietic progenitors.
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PMID:Hematopoietic cytokine-dependent differentiation to eosinophils and neutrophils in a newly established acute promyelocytic leukemia cell line with t(15;17). 947 3

Fifty-five patients with advanced multiple myeloma received purified CD34-selected peripheral blood progenitor cell transplants following myeloablative chemotherapy. A median of 4.1 x 10(6) CD34 cells/kg (range 1.2-30.7) were infused after busulfan (14 mg/kg) and cyclophosphamide (120 mg/kg); granulocyte-macrophage colony-stimulating factor was used until hematopoietic recovery. Median time to neutrophils >0.5 x 10(9)/l and platelets >20 x 10(9)/l were 12 days (range 10-16 and 8-184 days, respectively). Median follow-up of survivors from the time of transplantation is 33 months (range 7 to 44 months). Thirty-one patients are alive, 19 progression-free. Median progression-free survival is 14 months. Actuarial 3-year progression-free and overall survival are 29+/-14% and 47+/-17%. CD34-selection of peripheral blood progenitor cells provides effective hematopoietic support with significant progression-free and overall survival.
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PMID:Autologous CD34-selected blood progenitor cell transplants for patients with advanced multiple myeloma. 948 25

Bone marrow dendritic cells (DC) from patients with multiple myeloma (MM) were recently reported to be infected with Kaposi's sarcoma-associated herpesvirus (KSHV). Because immunotherapy strategies using DC are very promising in this disease, we looked for KSHV DNA in clinical-grade DC generated in vitro from MM patients. Adherent apheresis cells from MM patients were maintained for 7 days in clinical-grade X-VIVO 15 culture medium supplemented with granulocyte-macrophage colony-stimulating factor, interleukin-4, or interleukin-13. Tumor necrosis factor alpha was added for the last 2 days. We obtained a cell population with a DC phenotype able to endocytose fluorescein isothiocyanate (FITC)-dextran and efficiently activate resting allogenic T lymphocytes. To detect KSHV DNA, we used polymerase chain reaction (PCR) followed by Southern blotting of PCR product with a sensitivity detecting a few copies of viral DNA. All the PCR were repeated in a blinded fashion three times, on 1 mug and 0.2 mug of genomic DNA, in two different laboratories. Clinical-grade DC from 10 (91%) of 11 patients were not infected with KSHV. The apheresis cells and the purified CD34(+) cells from the same patients were also negative. A very weak PCR band was detected with DC from one patient, but the initial apheresis cells were negative. The detection of KSHV infection in 1 (9%) of 11 MM patients probably represents background seroprevalence. It seems likely that functional and clinical-grade DC from MM patients can safely be used in clinical trials.
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PMID:Clinical-grade functional dendritic cells from patients with multiple myeloma are not infected with Kaposi's sarcoma-associated herpesvirus. 973 Oct 82

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

Macrophages and dendritic cells derive from a hematopoietic stem cell and the existence of a common committed progenitor has been hypothesized. We have recently found in normal human marrow a subset of CD34(+) cells that constitutively expresses HLA-DR and low levels of CD86, a natural ligand for the T cell costimulation receptor CD28. This CD34(+) subset can elicit responses from allogeneic T cells. In this study, we show that CD34(+)/CD86(+) cells can also present tetanus toxoid antigen to memory CD4(+) T cells. CD86 is expressed at low levels in macrophages and high levels in dendritic cells. Therefore, we have tested the hypothesis that CD34(+)/CD86(+) cells are the common precursors of both macrophages and dendritic cells. CD34(+)/CD86(+) marrow cells cultured in granulocyte-macrophage colony-stimulating factor (GM-CSF)-generated macrophages. In contrast, CD34(+)/CD86(-) cells cultured in GM-CSF generated a predominant population of granulocytes. CD34(+)/CD86(+) cells cultured in GM-CSF plus tumor necrosis factor-alpha (TNF-alpha) generated almost exclusively CD1a+/CD83(+) dendritic cells. In contrast, CD34(+)/CD86(-) cells cultured in GM-CSF plus TNF-alpha generated a variety of cell types, including a small population of dendritic cells. In addition, CD34(+)/CD86(+) cells cultured in granulocyte colony-stimulating factor failed to generate CD15(+) granulocytes. Therefore, CD34(+)/CD86(+) cells are committed precursors of both macrophages and dendritic cells. The ontogeny of dendritic cells was recapitulated by stimulation of CD34(+)/CD86(-) cells with TNF-alpha that induced expression of CD86. Subsequent costimulation of CD86(+) cells with GM-CSF plus TNF-alpha lead to expression of CD83 and produced terminal dendritic cell differentiation. Thus, expression of CD86 on hematopoietic progenitor cells is regulated by TNF-alpha and denotes differentiation towards the macrophage or dendritic cell lineages.
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PMID:Expression of CD86 on human marrow CD34(+) cells identifies immunocompetent committed precursors of macrophages and dendritic cells. 957 27

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

p40/LAIR-1, a member of the immunoglobulin superfamily, is a surface molecule broadly distributed among leukocytes which has been shown to down-regulate T and NK cell activation. In this study, we show that p40/LAIR-1 is highly expressed in CD14+ peripheral blood mononuclear cells (PBMC). When cultured in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) for 10-14 days, CD14+ cells acquired morphologic and phenotypic features (i.e. loss of CD14 and expression of CD80bright and CD86bright) typical of dendritic cells (DC) and lost the expression of p40/LAIR-1. Engagement of p40/LAIR-1 (but not of CD58) by specific monoclonal antibodies prevented CD14+ PBMC differentiation into DC; when cultured in the presence of GM- CSF upon p40/LAIR-1 cross-linking, the resulting cells were CD14+CD80(dull)CD86(dull) and displayed a macrophage-like morphology. We have recently demonstrated that peripheral blood CD14+ cells co-expressing the CD34 progenitor marker represent the circulating precursors of CD83+ DC. Herein we show that cross-linking of p40/LAIR-1 prevented the maturation of CD14+CD34+ cells into CD83+ DC. This effect appears to be consequent to the impairment of GM-CSF receptor-mediated activation signaling. Indeed, triggering of GM-CSF receptors in both CD14+ and CD14+CD34+ cells led to increases in the intracellular free calcium concentrations which were inhibited by p40/LAIR-1 engagement. Taken together, these data suggest a possible regulating role played by p40/LAIR-1 in the process of differentiation from peripheral blood precursors into DC induced by GM-CSF.
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PMID:p40/LAIR-1 regulates the differentiation of peripheral blood precursors to dendritic cells induced by granulocyte-monocyte colony-stimulating factor. 969 76

Adoptive immunotherapy with donor lymphocyte infusions (DLI) is an effective treatment for relapsed chronic myeloid leukemia (CML) after allogeneic stem cell transplantation. To identify the effector and target cell populations responsible for the elimination of the leukemic cells in vivo we developed an assay to measure the frequency of T lymphocyte precursor cells capable of suppressing leukemic progenitor cells. Target cells in this assay were CML cells that were cultured in the presence of stem cell factor, interleukin 3, granulocyte-macrophage colony-stimulating factor, granulocyte colony-stimulating factor, and erythropoietin. [3H]thymidine incorporation at day 7 represented the proliferation of the progeny of the CD34(+) CML progenitor cells, and not of the more mature CD34(-) CML cells. Effector cells were mononuclear cells, which were used in a limiting dilution analysis to measure the frequencies of CML progenitor cell-inhibitory lymphocyte precursors (PCILp) in peripheral blood of seven patients before and after DLI for relapsed CML. In the six patients who entered complete remission, a 5- to 100-fold increase of PCILp was found during the clinical response. In the patient with resistant relapse the frequency of PCILp was <10 per ml before and after DLI. Leukemia-reactive helper T lymphocyte precursor frequencies remained unchanged after DLI. A significant increase in cytotoxic T lymphocyte precursor frequency against more mature leukemic cells was found in only two responding patients. These results indicate that T cells specifically directed against CD34(+) CML progenitor cells mediate the antileukemic effect of DLI.
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PMID:T cells recognizing leukemic CD34(+) progenitor cells mediate the antileukemic effect of donor lymphocyte infusions for relapsed chronic myeloid leukemia after allogeneic stem cell transplantation. 970 16


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