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PubMed1980

Lithium and T cell colonies.

In humans, therapeutic doses of lithium causes granulocytosis and lymphopenia. In vitro increased numbers of colony forming units (CFU-GM) are observed. The effect of lithium on lymphocyte colonies is unknown. We grew T cell colonies from normal individuals and patients who were on lithium only and found that T cell colony numbers were decreased in patients who were taking lithium. Recent evidence suggests that there is a PRECURSOR common to the granulocytic and lymphocytic cell lines. Since lithium causes increased granulocytic colonies and seems to decrease lymphocyte colonies we propose that lithium may have an effect on the precursor cell resulting in preferentially shifting maturation from the lymphocytic to the granulocytic series.

Hematopoietic Stem Cells↗

PubMed1984

[Effect of bone marrow cells on the clonal growth of granulocyte-macrophage precursors in a soft agar].

The granulocyte-macrophage colony stimulating effect of bone marrow cells is shown to be less intensive than the stimulating effect of feeding leukocytes. It is supposed that these two stimulating substances activate different progenitor populations. Stimulating effect of mixture consisting of leukocytes and bone marrow cells are very close to that of bone marrow cells alone. Leukemic bone marrow cells demonstrate the least colony stimulating ability.

Agar↗

PubMed1985

Release of granulocyte-macrophage colony-inhibiting activity by normal human postthymic precursor cells.

Seven normal human peripheral blood cell fractions (buffy coat, mononuclear cells, non-T, T, Fc-IgM receptor-depleted T-lymphocyte, Fc-IgG receptor-depleted T-lymphocyte, and autologous rosette-forming T-cell-depleted T-lymphocyte subpopulations) treated with phytohemagglutinin (PHA) were examined for the production of granulocyte-macrophage colony-stimulating activity (CSA). It was found that medium conditioned by a T-lymphocyte subpopulation depleted of autologous rosette-forming T-cells (Tar cells, a postthymic precursor subpopulation that inhibits Ig synthesis) stimulated colony-forming units of granulocyte and macrophages (CFU-GM) to a greater extent than did the other conditioned media (CM) analyzed. Based on this finding, CM from an enriched Tar subpopulation was prepared and thus showed that PHA-treated Tar cells release a factor capable of inhibiting CFU-GM growth. The inhibitory activity of this factor persisted-after heat inactivation, suggesting that cause of the colony-inhibiting activity (CIA) is other than interferon. Further studies revealed that Tar-derived inhibitory factor acts either directly upon CFU-GM or via monocytes/macrophages (M phi/Ma), enhancing CIA, and not the level of CSA production by M phi/Ma. The overall data are interpreted as demonstrating the presence of CIA in a specific T-lymphocyte subpopulation that may represent a new relationship between lymphocytic and myelocytic systems in the human.

Colony-Forming Units Assay↗

PubMedDate not supplied

Molecular cloning and expression of cDNA for human granulocyte colony-stimulating factor.

Granulocyte colony-stimulating factor (G-CSF) is a member of the CSF family of hormone-like glycoproteins that regulate haematopoietic cell proliferation and differentiation, and G-CSF almost exclusively stimulates the colony formation of granulocytes from committed precursor cells in semi-solid agar culture. Recently, Nomura et al. have established a human squamous carcinoma cell line (designated CHU-2) from a human oral cavity tumour which produces large quantities of CSF constitutively, and the CSF produced by CHU-2 cells has been purified to homogeneity from the conditioned medium. We have now determined the partial amino-acid sequence of the purified G-CSF protein, and by using oligonucleotides as probes, have isolated several clones containing G-CSF complementary DNA from the cDNA library prepared with messenger RNA from CHU-2 cells. The complete nucleotide sequences of two of these cDNAs were determined and the expression of the cDNA in monkey COS cells gave rise to a protein showing authentic G-CSF activity. Furthermore, Southern hybridization analysis of DNA from normal leukocytes and CHU-2 cells suggests that the human genome contains only one gene for G-CSF and that some rearrangement has occurred within one of the alleles of the G-CSF gene in CHU-2 cells.

Amino Acid Sequence↗

PubMed1985

In vitro natural cell-mediated cytotoxicity against Candida albicans: macrophage precursors as effector cells.

Bone marrow cells, cultured in L-929 CSF, consist of cells of granulocyte and macrophage lineages. Cells of the granulocyte lineage are known to be cytotoxic for Candida albicans. In this paper we report that macrophage precursor cells also display strong cell-mediated cytotoxicity against the yeast form of the dimorphic fungus C. albicans. The macrophage precursors responsible for this activity are nylon wool-nonadherent, nonphagocytic cells and lack asialo GM1 surface antigen. A purified population of macrophage precursors (greater than 95%) was obtained by means of Percoll density centrifugation. The interaction of these purified effectors with the target yeast cells was analyzed at a single cell level, and their activity was compared with that displayed by cells of the granulocytic series derived from the same bone marrow culture. Macrophage precursor cells proved to be more effective in binding the target cells and showed the same killing ability as the granulocytes: macrophage precursors were not damaged by contact with the target, in contrast to that which happened with granulocytes. In a long-term colony-forming unit assay, in fact, granulocytic cells showed a decrease over time in their ability to inhibit the growth of C. albicans, probably due to cell damage and death after the interaction with the target. In contrast, no loss of activity was observed with the macrophage precursor fraction. The same macrophage precursor cells also proved able to exert good natural killer activity against YAC-1 lymphoma cells, but not against P815 mastocytoma cells, as reported previously. The macrophage precursor cells, when cultivated in vitro to mature macrophages, lost completely their natural cytotoxicity against C. albicans and YAC-1 cells. The implications of these findings, as well as the possible role in vivo of such a precursor cell population during an infection, are discussed.

Animals↗

PubMed1982

Residual injury to the hemopoietic microenvironment following sequential radiation and busulfan.

Our earlier studies in mice showed that sequential radiation and cyclophosphamide suppressed marrow stromal cells (MSC) and prevented local hemopoietic repopulation for several months. Because others have shown that busulfan administration caused marrow aplasia, we studied its ability, combined with radiation, to produce a persistent microenvironmental defect in mice. Intraperitoneal administration of four weekly doses of 20 mg/kg busulfan, starting one week after 1500 rad leg irradiation, produced a severe microenvironmental lesion for 6 months reflected by lack of repopulation in femoral marrow to greater than 50% of normal by MSC, hemopoietic stem cells (CFU-S), and granulocyte-macrophage precursors. Differential marrow cell counts revealed that precursors of hemopoietic cells were more profoundly affected than their progeny. Hemopoietic stem cells and MSC failed to recover in busulfan-treated mice at 6 months to the same extent as those treated with cyclophosphamide. In addition, the busulfan-treated mice had an excessive number of myeloid blast cells and a severe erythroid depletion suggesting that these animals were preleukemic. We conclude that: 1) sequential radiation and busulfan administration caused long-term microenvironmental damage reflected by incomplete repopulation of the femoral marrow and suppression of MSC, and 2) multiple courses of busulfan prevented hemopoietic repopulation longer than a similar regimen of cyclophosphamide.

Animals↗

PubMed1998

Pseudo-Gaucher histiocytes identified up to 1 year after transplantation for CML are BCR/ABL-positive.

The results of polymerase chain reaction (PCR) analysis after transplantation for chronic myelogenous leukemia (CML) are difficult to interpret clinically. Positive findings for BCR/ABL can be seen not only in patients who go on to relapse but also in patients who, after years of follow-up, remain in complete remission. The cause for the lack of concordance between PCR findings and relapse is not clear. We identified two patients with CML who had rare pseudo-Gaucher cells in their bone marrow aspirate specimens prior to, and at 1, and 6 or 12 months following syngeneic or allogeneic hematopoietic transplantation. After the transplant, the patients obtained clinical remission and were shown to be cytogenetically normal and to have germline MBCR in blood or bone marrow by Southern analysis. One patient was PCR-positive for BCR/ABL in the marrow at 12 months. In order to determine whether the pseudo-Gaucher histiocytes were BCR/ABL-positive, we used fluorescence in situ hybridization and probes for MBCR and ABL and analyzed Wright-stained smears to correlate molecular cytogenetic findings with cell type. On three aspirate smears from each patient (at 6 or 12 months post-transplant), all of the pseudo-Gaucher cells studied (10/10 in one patient and 12/12 in the other) showed the fusion for BCR/ABL. Other cells analyzed randomly (erythroid precursors, granulocytes and rare monocytes, lymphocytes and plasma cells) did not. Our cases provide the first proof that pseudo-Gaucher cells carry the BCR/ABL fusion. Furthermore, they illustrate that these cells can be found in the marrow for up to 12 months following transplantation. Our results permit speculation that pseudo-Gaucher cells or other long-lived histocytes may be one cause of persistent PCR positivity after transplantation that is not predictive of disease relapse.

Adult↗

PubMed1986

Regulation of expression of the interleukin-2 receptor on hematopoietic cells by interleukin-3.

Remarkable similarities in the intracellular and genetic events occur when lymphoid and hematopoietic cells are exposed to their specific growth factors. The interleukin-2 (IL-2) receptor, whose cell-surface expression is an absolute requirement for the growth and differentiation of lymphoid cells, was detected on various nonlymphoid hematopoietic cell types in this study. Cell lines consisting either of granulocyte-macrophage precursors or mast cells, which are dependent on interleukin-3 (IL-3) for their growth, expressed high levels of the IL-2 receptor on their surface. Analysis of the binding characteristics of these receptors with 125I-labeled recombinant IL-2 revealed that only receptors with low affinity for IL-2 were present on these cells. Addition of purified recombinant IL-3 to these cell lines led to an increase in IL-2 receptor gene expression within 1 hour in isolated nuclei. This IL-3--induced increase in the number of IL-2 receptors on the cell surface is maximal within 24 hours. Addition of 10,000 units of IL-2 to these cells had no apparent effect on their growth or differentiation. The presence of the receptor with only low affinity for IL-2 on hematopoietic cells and the regulation by IL-3 suggest that this receptor is involved in some important metabolic event in hematopoiesis.

Animals↗

PubMed1993

Fine-needle aspiration cytology of extramedullary hematopoiesis (myeloid metaplasia).

Myeloproliferative disease may be associated with extramedullary hematopoiesis (EH). Clinically, however, the differential diagnosis of solid masses in these patients includes not only EH but also inflammatory lesions and malignant neoplasms, including granulocytic sarcoma. We report the fine-needle aspiration (FNA) cytology of extramedullary hematopoiesis in five patients with a history of myeloproliferative disease. All of the masses developed subsequent to the diagnosis of myeloproliferative disease. Two of the patients had chronic myelogenous leukemia, one had essential thrombocythemia, and two had an unspecified chronic myeloproliferative disorder. The patients ranged in age from 50 to 88 years, and all presented with solid masses involving the kidney (two aspirates), liver (one aspirate), and lymph nodes (three aspirates). One of the lymph node aspirates was from a paratracheal lymph node. Cytologically, the lesions were composed of varying numbers of hematopoietic cells from all three hematologic cell lines. The Diff-Quik stain was especially helpful in the recognition of the hematopoietic cells such as granulocytic precursors, eosinophils, and megakaryocytes. In several cases, the megakaryocytic component was particularly prominent. In one case, the Factor VIII immunoperoxidase stain was used to confirm the megakaryocytic lineage of the multinucleated cells. The cytologic differential diagnosis, which includes granulocytic sarcoma, inflammatory disorders, and other lesions containing multinucleated giant cells, is discussed.

Aged↗

PubMed2005

Crystallization of a 2:2 complex of granulocyte-colony stimulating factor (GCSF) with the ligand-binding region of the GCSF receptor.

The granulocyte-colony stimulating factor (GCSF) receptor receives signals for regulating the maturation, proliferation and differentiation of the precursor cells of neutrophilic granulocytes. The signalling complex composed of two GCSFs (GCSF, 19 kDa) and two GCSF receptors (GCSFR, 34 kDa) consisting of an Ig-like domain and a cytokine-receptor homologous (CRH) domain was crystallized. A crystal of the complex was grown in 1.0 M sodium formate and 0.1 M sodium acetate pH 4.6 and belongs to space group P4(1)2(1)2 (or its enantiomorph P4(3)2(1)2), with unit-cell parameters a = b = 110.1, c = 331.8 A. Unfortunately, this crystal form did not diffract beyond 5 A resolution. Since the heterogeneity of GCSF receptor appeared to prevent the growth of good-quality crystals, the GCSF receptor was fractionated by anion-exchange chromatography. Crystals of the GCSF-fractionated GCSF receptor complex were grown as a new crystal form in 0.2 M ammonium phosphate. This new crystal form diffracted to beyond 3.0 A resolution and belonged to space group P3(1)21 (or its enantiomorph P3(2)21), with unit-cell parameters a = b = 134.8, c = 105.7 A.

Chromatography, Ion Exchange↗

PubMed1991

The monoclonal antibody 11G7 recognizes a novel differentiation antigen expressed on hemopoietic precursor cells.

A monoclonal antibody (11G7) detecting a novel antigen on human hemopoietic progenitor cells (named 11G7R = 11G7 receptor) was raised by immunization of a Balb/c mouse with the leukemic blasts of a patient suffering from chronic myelogenous leukemia blast crisis (CML-BC). The antigen is expressed on most of MHC class II bearing peripheral blood leucocytes (PBL) and on a subpopulation of bone marrow mononuclear cells (BMMNC). By FACS-sorting and colony assays, it could be demonstrated that 11G7R is expressed on myelo-monocytic and myelo-granulocytic bone marrow precursor cells (GM-CFC, G-CFC, M-CFC) but is absent from erythroid precursor cells (BFU-E) and on cells exhibiting the capacity to form mixed colonies (GEMM-CFC). Double-fluorescence analysis on BMMNC revealed that 11G7R is expressed on a subset of B-cells, myeloid cells and cells carrying the HPCA-1 antigen (CD34). It has a similar distribution pattern to the myeloid antigens CD13 and CD33. However, in contrast to these antigens, 11G7R is also expressed on the blasts of several lymphoid leukemias (4/9 B-ALL, 1/2 T-ALL) and therefore it is not restricted to the myeloid lineage.

Animals↗

PubMed1988

Recombinant human granulocyte-macrophage colony-stimulating factor induces secretion of autoinhibitory monokines by U-937 cells.

Colony-stimulating factors are required for survival proliferation, differentiation and functional activation of granulocytes, macrophages and their precursor cells. In the present report, however, we demonstrate antiproliferative activity of recombinant human (rh) granulocyte-macrophage colony-stimulating factor (GM-CSF) on monoblast cell line U-937 and provide evidence for the involvement of tumor necrosis factor alpha TNF-alpha and interleukin 1 beta (IL 1 beta) in its growth inhibitory action. GM-CSF (but not granulocyte CSF, G-CSF or macrophage CSF, M-CSF) suppressed DNA synthesis and self renewal of U-937 cells. Similarly, medium conditioned by U-937 cells in response to GM-CSF (GM-CSF U-937-CM) was able to reduce clonogenicity and [3H]thymidine uptake by U-937 cells. Since neutralization of GM-CSF present in GM-CSF U-937-CM by monoclonal antibody to GM-CSF did not abrogate the autoinhibitory activity present in GM-CSF U-937-CM, we considered the possibility that other soluble molecules are released by U-937 cells upon GM-CSF stimulation. Neutralization by antibodies to IL 1 beta and TNF-alpha suggested that both monokines could be the antiproliferative principle operating in GM-CSF U-937-CM. Moreover, employing IL 1 beta-specific enzyme-linked immunosorbent assay, TNF-alpha specific radioimmunoassay, Northern analysis using a cloned TNF-alpha-specific cDNA and an oligonucleotide probe for IL 1 beta, we demonstrate GM-CSF-inducible IL 1 beta and TNF-alpha gene expression by U-937 cells at the mRNA and protein level. Although M-CSF expression was induced under similar conditions, M-CSF failed to inhibit growth of U-937 cells.

Adult↗

PubMed1999

Atomic structure of the GCSF-receptor complex showing a new cytokine-receptor recognition scheme.

Granulocyte colony-stimulating factor (GCSF) is the principal growth factor regulating the maturation, proliferation and differentiation of the precursor cells of neutrophilic granulocytes and is used to treat neutropenia. GCSF is a member of the long-chain subtype of the class 1 cytokine superfamily, which includes growth hormone, erythropoietin, interleukin 6 and oncostatin M. Here we have determined the crystal structure of GCSF complexed to the BN-BC domains, the principal ligand-binding region of the GCSF receptor (GCSFR). The two receptor domains form a complex in a 2:2 ratio with the ligand, with a non-crystallographic pseudo-twofold axis through primarily the interdomain region and secondarily the BC domain. This structural view of a gp130-type receptor-ligand complex presents a new molecular basis for cytokine-receptor recognition.

Amino Acid Sequence↗

PubMedDate not supplied

Granulocyte-macrophage colony-stimulating factor: pleiotropic cytokine with potential clinical usefulness.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a 23-kDa glycoprotein with remarkably diverse effects on immune and nonimmune cells. GM-CSF induces differentiation of granulocyte, macrophage, and eosinophil precursor cells. Proliferation of monocyte-macrophages, T lymphocytes, keratinocytes, and endothelial cells is also stimulated by GM-CSF. In addition, GM-CSF alters the functional properties of mature granulocytes, macrophages, eosinophils, and basophils. GM-CSF is produced by T lymphocytes, macrophages, and several cell types in extramedullary sites, where it may act in a paracrine manner to regulate the local response to antigenic challenge. Clinical trials of GM-CSF have been conducted in patients with AIDS, aplastic anemia, myelodysplastic syndromes, and sarcoma and following bone marrow transplantation and accidental radiation exposure. GM-CSF significantly increased circulating numbers of several myeloid cells and produced dose-dependent toxicity consisting primarily of myalgias, fever, fluid retention, and serosal effusions. Additional studies are needed to define the role of GM-CSF in treatment of patients with qualitative and quantitative dysfunction of immune cells.

Animals↗

PubMedDate not supplied

In vitro and in vivo assessment of the viability of cryopreserved postmortem murine bone marrow cells.

The viability of cryopreserved mouse fresh and postmortem bone marrow cells was studied using methylcellulose clonal cell culture assay and the murine spleen colony technique. This study clearly indicates the presence of pluripotent hemopoietic stem cells in cryopreserved murine postmortem bone marrow cells. The viability of granulocytic precursors in both fresh and postmortem bone marrow cells was mildly to moderately decreased by the freezing process, while the proliferative capacity of erythrocytic stem cells is significantly decreased by cryopreservation. The results strongly suggest that frozen, fresh and cadaveric bone marrow bank for bone marrow transplantation may be of value.

Animals↗

PubMed1976

Properties of blast cells in 'control' cultures of human blood lymphocytes. Preliminary note.

Ficoll-Hypaque separated normal human peripheral blood lymphocytes undergo appreciable blastogenesis in RPMI 1640-pooled human serum or - autologous plasma. During the 1st week, granulated blasts with peroixdase activity and ultrastructural properties of granulocytes precursors appear. These cells, which appear to be relateed to CFC (colony-forming cells), contribute to the mitotic population in these unstimulated "control" cultures prior to 6 days.

Colony-Stimulating Factors↗

PubMed2002

[Ligand recognition mechanism of G-CSF receptor and metabotropic glutamate receptor].

A three-dimensional view of ligand-receptor recognition at the atomic level is crucial to understand the molecular mechanism of receptor activation. This review describes the structure-function relationships of two receptors important for pharmaceutical science. Granulocyte colony-stimulating factor (G-CSF) is the principal growth factor regulating the maturation, proliferation, and differentiation of the precursor cells of neutrophilic granulocytes. We have determined the crystal structure of G-CSF complexed to the BN-BC domains, the principal ligand binding region of the G-CSF receptor. In a novel oligomerization scheme, the two receptor domains complex in a 2:2 ratio to the ligand, with a noncrystallographic pseudo-two-fold axis through primarily the interdomain region and secondarily the BC domain. This first structural view of a gp130-type receptor-ligand complex presents a new molecular basis for cytokine-receptor recognition. The metabotropic glutamate receptors (mGluRs) are key receptors in the modulation of excitatory synaptic transmission in the central nervous system. Three different crystal structures of the extracellular ligand-binding region (LBR) of mGluR1 have been determined, in a complex with glutamate and in two unliganded forms. They all showed disulfide-linked homo-dimers, of which the "active" and "resting" conformations are modulated through the novel dimeric interface by a packed alpha-helical structure. The bilobed protomer architectures flexibly change their domain arrangements between an "open" or "closed" conformation. Glutamate binding stabilizes both the "active" dimer and "closed" protomer in dynamic equilibrium. Four domain movements within the dimer affect the separation of the transmembrane and intracellular regions and thereby activate the receptor.

Animals↗

PubMed1988

Characterization of the priming effects of human granulocyte-macrophage colony-stimulating factor on human neutrophil leukotriene synthesis.

Human granulocyte-macrophage colony-stimulating factor (GM-CSF) is an in vitro and in vivo stimulator of human bone marrow myelomonocytic precursor cells and mature granulocyte and macrophage effector cells. We have compared the effect of GM-CSF on the synthesis of 5-lipoxygenase products induced by the chemotactic peptide fMet-Leu-Phe and the calcium ionophore A23187 in human neutrophils. Although GM-CSF alone did not stimulate detectable synthesis of products of the 5-lipoxygenase pathway, pre-incubation of neutrophils with 200 pM GM-CSF for 1 hour at 23 degrees C enhanced synthesis of leukotriene B4, its all-trans isomers and omega-oxidation products, and 5-hydroxyeicosatetraenoic acid in response to both the calcium ionophore A23187 (1.5 microM), and the chemotactic peptide fMet-Leu-Phe (0.1 microM). This priming effect of GM-CSF was maximal after a 60 min incubation at 23 degrees C, or after a 30 min preincubation at 37 degrees C. The effect of GM-CSF was maximal using a concentration of 1 nM. Enhancement of the leukotriene synthesis stimulated by A23187 was only observed when the cells were stimulated by the ionophore for periods of 3 minutes or less. In contrast, the enhancing effect of GM-CSF was still apparent when cells were exposed to fMet-Leu-Phe for as long as 15 minutes. Furthermore, the enhancing effect of GM-CSF was ablated when neutrophils were stimulated with A23187 and exogenous arachidonic acid. However, co-addition of exogenous arachidonic acid with fMet-Leu-Phe did not entirely mask the effect of GM-CSF. Possible mechanisms of action of GM-CSF are discussed.

Arachidonate 5-Lipoxygenase↗