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Biomedical subjects

D Metcalf

Publications and source records attributed to D Metcalf.

At least 181 records · Page 10Linked to original sources
PubMed1990

Effects of injected leukemia inhibitory factor on hematopoietic and other tissues in mice.

Purified bacterially synthesized recombinant murine leukemia inhibitory factor (LIF) was injected in varying doses for up to 2 weeks into adult DBA/2 and C3H/HeJ mice. At high doses (2 micrograms, three times daily) LIF exhibited toxic effects seen as behavioral changes, loss of body fat, and thymus atrophy. Dose-related rises were observed in blood platelets, erythrocyte sedimentation rates, and serum calcium to albumin ratios, including dose schedules with no toxic effects. LIF induced a decrease in bone marrow cell numbers, particularly in marrow lymphocytes, and a moderate increase in spleen weight with a reduction in spleen lymphocytes and an elevation of erythroid populations. LIF-injected mice showed a rise in megakaryocytes up to twofold in the marrow and fivefold in the spleen, with an associated 10-fold rise in megakaryocyte progenitor cells in the spleen. Comparable rises in other types of progenitor cells were also observed in the spleen. The observed changes indicate the biologic activity of LIF in vivo and are consistent with the known wide range of in vitro actions of this molecule. The ability of LIF to elevate megakaryocyte and platelet levels suggests a potential clinical application of LIF in the treatment of thrombocytopenias.

Adipose Tissue↗
PubMed1990

The induction and inhibition of differentiation in normal and leukaemic cells.

For granulocytic-macrophage progenitor populations and their progeny, five glycoproteins have been identified: GM-CSF, G-CSF, multi-CSF, M-CSF and IL-6 that can regulate their proliferative activity, maturation and functional activities. The same glycoproteins also have a capacity to induce irreversible differentiation commitment in normal bipotential granulocyte-macrophage progenitors and in some myeloid leukaemic cell lines, which suggests that common cellular processes exist in both situations. The leukaemia inhibitory factor (LIF) is a glycoprotein, with intriguing properties, which can either induce differentiation in some myeloid leukaemic cell lines or prevent differentiation in normal totipotential embryonic stem cells. The data from the LIF studies suggest a genetic mechanism controlling self-generation that is relatively simple and may be common to all cells. However, the actual cellular response observed appears to depend on the nature of the responding cell.

Animals↗
PubMed1990

Enhanced suppression of human myeloid leukemic cell lines by combinations of IL-6, LIF, GM-CSF and G-CSF.

The interactions of purified recombinant human leukemia inhibitory factor (LIF), interleukin-6 (IL-6), granulocyte colony stimulating factor (G-CSF), and granulocyte-macrophage CSF (GM-CSF) on the clonogenicity of HL60 cells and U937 cells were studied in vitro. IL-6 alone strongly suppressed colony formation by U937 cells with induction of differentiation and loss of clonogenicity. GM-CSF interacted synergistically with IL-6 to further reduce colony number and suppress the growth of clonogenic cells formed by HL60 and U937 cells. LIF synergized with IL-6 to reduce colony number and enhance the suppression of the clonogenic U937 cells. The results suggest that these 4 glycoproteins, acting alone or in combination, may be able to suppress human leukemia cells of appropriate type and be of value in the clinical management of myeloid leukemia.

Colony-Stimulating Factors↗
PubMed1990

Effects of irradiation of recipient mice on the behavior and leukemogenic potential of factor-dependent hematopoietic cell lines.

After intravenous (IV) injection with factor-dependent FDC-P1 cells, irradiated DBA/2 and BALB/c mice developed transplantable leukemias owing to neoplastic transformation of the injected cells in vivo. Increasing the radiation dose shortened the preleukemic latent period, and in female mice the frequency of leukemia development was higher and the latent period shorter than in male mice. In the preleukemic period, the injected FDC-P1 cells rapidly increased in number in hematopoietic organs of irradiated animals, reaching peak levels 3 to 5 weeks after injection; factor-independent transformed cells were not detected before day 45. In unirradiated animals, these events were delayed by several weeks, and long-term survivors did not harbor detectable FDC-P1 cells. FDC-P1 cells sampled from preleukemic mice frequently showed atypical colony formation and reduced cloning efficiency in vitro, suggesting the occurrence of a distinct preleukemic change. U16.6 cells produced leukemia only in irradiated recipients, and the leukemic cells usually remained factor dependent. The two contrasting models should be of value in further analyzing the mechanisms underlying radiation-induced leukemias.

Animals↗
PubMed1990

Osteoblasts display receptors for and responses to leukemia-inhibitory factor.

Specific binding of leukemia-inhibitory factor (LIF) to osteoblasts, but not multinucleated osteoclasts, was demonstrated by receptor autoradiography by using cells isolated from newborn rat long bones. The clonal rat osteogenic sarcoma cells, UMR 106-06, which have several phenotypic properties of osteoblasts, expressed 300 LIF receptors per cell, with an apparent KD of 60 pM. Treatment of calvarial osteoblasts or UMR 106-01 cells with LIF resulted in a dose-dependent inhibition of plasminogen activator (PA) activity. Both calvarial osteoblasts and osteogenic sarcoma cells were shown by Western blotting and reverse fibrin autography to produce plasminogen activator inhibitor-1 (PAI-1), the production of which was increased by LIF treatment. Northern blot analysis revealed that LIF treatment resulted in a rapid (peak 1 hour), dose-dependent increase in mRNA for PAI-1. LIF treatment of the preosteoblast cell line, UMR 201, enhanced the alkaline phosphatase response of these cells to retinoic acid. Each of the osteoblast-like cell types (calvarial osteoblasts, UMR 106-06, and UMR 201) was shown to produce LIF by bioassay and, by using the polymerase chain reaction (PCR), was shown to express low levels of mRNA for LIF. These data establish that cells of the osteoblast lineage are targets for LIF action. The reported anabolic effects of this cytokine on bone formation in vivo could be related to inhibition of protease activity. LIF may be an important paracrine modulator in bone, or perhaps an autocrine one, based on the evidence for its production by osteoblasts and osteoblast-like cells.

Alkaline Phosphatase↗
PubMed1990

Disease states induced by hemopoietic growth factor excess: their implications in medicine.

Sustained excess levels of hemopoietic regulators can induce a variety of disease states in mice in addition to the anticipated hyperplasia of the responding hemopoietic lineages. In all the models examined so far, there is a complicating problem that at least some responding cells are also producing the excess regulator concerned. The development of the various disease states may therefore not necessarily be the simple consequence of overstimulation by excess regulator levels. The various disease states develop rapidly in a high proportion of animals and should serve as useful models for a variety of disease states in man.

Animals↗
PubMed1990

Changes in hemopoietic and regulator levels in mice during fatal or nonfatal malarial infections. I. Erythropoietic populations.

Erythroid precursors BFU-E and CFU-E and erythroblasts (ERB) were monitored in the marrow and spleen of mice during fatal or nonfatal malaria. Transient depletions of marrow CFU-E and ERB without modification of BFU-E or erythropoietin (Epo) levels were found as early events in fatal infections. Before anemia development, erythropoiesis was reduced in the bone marrow but increased in the spleen. During the anemic phase, for comparable levels of anemia, plasma Epo levels were elevated to a similar degree in fatal and nonfatal malaria. In the bone marrow, CFU-E increased twofold and BFU-E were usually reduced as expected in severe anemia. ERB populations increased but remained below or within normal values, suggesting an impairment of marrow erythropoiesis related to early events following infection. In contrast, in the spleen, ERB production was strongly simulated but amplification of ERB, CFU-E, and BFU-E populations was 2.5-fold lower in fatal than in nonfatal malaria. The results suggest that a defect in amplification of splenic erythropoiesis is a crucial determinant of the fatal outcome of malarial infection. This may have been mediated by a defective stem cell migration or multiplication. Some evidence obtained during recovery stages suggested that a factor(s) other than Epo may control splenic erythropoiesis during the anemia associated with malaria.

Animals↗
PubMed1990

Changes in hemopoietic and regulator levels in mice during fatal or nonfatal malarial infections. II. Nonerythroid populations.

Levels of mature lymphocytes, granulocytes, macrophages, platelets, their progenitor cells, and cytokines were monitored in the blood, marrow, and spleen during fatal or nonfatal murine malarial infections. In all four malaria models, before anemia developed, there was a lymphopenia, a rapid lymphocyte depletion in the marrow with a compensating rise in spleen lymphocytes, thrombocytopenia with increased megakaryocytic progenitor cell numbers, and monocyte increases in the bone marrow and later the spleen. The development of anemia was associated with a monocytosis and neutropenia, an increase in granulomonocytic progenitor cells in the spleen, and a reduction of spleen lymphocytes. Spleen granulocytes, monocytes, and their progenitor cells increased two- to threefold more in nonfatal than in fatal malaria and the spleen lymphocyte pool became severely depleted in fatal malaria. The data suggest that a defective effector cell response was of importance for the fatal outcome of the disease. Other than an early rise in serum macrophage colony stimulating factor levels in fatal infections, changes in levels of the regulators of these effector cells did not correlate well with the outcome of the infection.

Animals↗
PubMed1990

Low-affinity placenta-derived receptors for human granulocyte-macrophage colony-stimulating factor can deliver a proliferative signal to murine hemopoietic cells.

Retrovirally mediated introduction of a cDNA encoding a placenta-derived low-affinity receptor for human granulocyte-macrophage colony-stimulating factor (GM-CSF) into murine FDC-P1 hemopoietic cells allowed these cells to proliferate when stimulated by human GM-CSF. The expressed human receptors on cloned lines were of low affinity (Kd = 4-6 nM), were internalized, and did not interact with endogenous GM-CSF receptors. Concentrations of human GM-CSF of 6.5-13 nM were required to stimulate 50% maximal colony formation versus a concentration of murine GM-CSF of 6 pM; this difference is comparable with the difference in relative affinities of the human and murine receptors for their respective ligands. If maintained in murine GM-CSF, cells able to bind or respond to human GM-CSF were rapidly lost due to transcriptional inactivation of the inserted cDNA. The observations indicate that low-affinity receptors for human GM-CSF can deliver a proliferative signal in appropriate cells and that the signaling mechanisms are not species-specific.

Animals↗
PubMed1990

Effect of recombinant human granulocyte-macrophage colony stimulating factor on progenitor cells in patients with advanced malignancies.

Haemopoietic progenitor cell levels were determined in the blood and marrow of 37 patients with advanced malignancies undergoing a phase I/II clinical trial of 0.3-30 micrograms/kg/d recombinant human granulocyte-macrophage colony stimulating factor (rGM-CSF). After injection of rGM-CSF, the absolute number of circulating progenitor cells fell initially but after 4 d of infusion a dose-dependent increase was observed in progenitor cells of all lineages with a slight bias favouring granulocyte-macrophage progenitors. A mean 8.4-fold increase in GM-CFC and a 3.3-fold increase in BFU-E were observed at a dose level of 20 micrograms/kg/d of rGM-CSF. Patients with malignant lymphoma showed a greater response than other patients at the same dose level and the CFU-E rise correlated with the haematocrit. This study suggests that GM-CSF may be of value in elevating circulating progenitor cells for subsequent autografting.

Adult↗
PubMed1990

The regulatory control of hemopoietic populations.

The identification and mass-production by recombinant technology of twelve of the regulatory glycoproteins controlling hemopoiesis has represented a major advance in understanding hemopoiesis and introduces the possibility of being able to correct major disease states involving hemopoietic cells. Information so far on the control of megakaryocyte formation indicates that this follows the general pattern operating for other hemopoietic subpopulations and the present conference will review the new knowledge of specific factors influencing megakaryocyte formation and function.

Animals↗
PubMed1990

Anti-bacterial activity of peritoneal cells from transgenic mice producing high levels of GM-CSF.

Two lines of transgenic mice carrying the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) produce vastly increased numbers of macrophages with abundant foamy cytoplasm resembling classical activated macrophages. Cells from both lines were negative for myeloperoxidase, a bactericidal enzyme found in monocytes as well as neutrophils, but not mature macrophages. Cells from the so called 'male line' produced greatly increased levels of oxygen degradation products in response to phagocytosis, compared with cells from the 'female line' or from normal littermates. The ability of the cells to phagocytose and lyse the intracellular bacterium Listeria monocytogenes was tested in vitro using radiolabelled organisms. Although the cells from transgenic mice were more highly phagocytic than cells from normal littermates, cells from either line were no more efficient than normal at lysing the bacteria they had phagocytosed. Nevertheless, because of the high phagocytic rate, more bacteria were exposed to lysis in the cells of transgenic mice, and the final outcome was a higher rate of bacteriolysis.

Animals↗
PubMed1989

Factors influencing the time and site of leukemic transformation of factor-dependent cells after injection into irradiated recipient mice.

After cells of the non-tumorigenic-factor-dependent line FDC-PI are injected into irradiated DBA/2 mice a progressive increase occurs in the number of engrafted FDC-PI cells and eventually leukemic transformation occurs. Step-wise increase in the number of cells injected led to an increasingly rapid accumulation of untransformed FDC-PI cells in the hemopoietic organs and some shortening of the pre-leukemic phase. FDC-PI cells explanted from pre-leukemic mice differed from primary FDC-PI cells in that they were able to undergo leukemic transformation in non-irradiated recipients after short latent periods. Pre-leukemic populations contained FDC-PI variants with an improved ability to proliferate in non-irradiated tissues. Co-injection of normal marrow cells delayed the leukemic transformation of injected FDC-PI cells. The accelerating effect of prior irradiation of the recipient on leukemia development was also abrogated when the injection of FDC-PI cells was delayed by several weeks. No specific site of transformation could be determined in mice with very early leukemias. Proliferation of untransformed FDC-PI cells and the emergence of variants with improved adaptation to in vivo conditions appear to be important and possibly necessary steps in the pathogenesis of the disease. Whether the host contributes actively to the final transformation process remains speculative.

Animals↗