Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002874 (aplastic anemia)
 5,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present multicenter study was undertaken to confirm whether filgrastim/recombinant human granulocyte colony stimulating factor (rhG-CSF) could mobilize residual multipotential stem cells by its G0-shortening effect in patients with aplastic anemia (AA) and induce a multilineage response. Twenty-seven patients with acquired severe or moderate AA received long-term administration (2 to 12+ months) of rhG-CSF in doses from 100 to 400 micrograms/body/day by s.c. injection or 250 to 1,500 micrograms/body/day by i.v. infusion. Twenty-six out of the 27 evaluable patients showed a substantial increase in neutrophils associated with a recovery of myeloid precursors in bone marrow within one month of therapy. Interestingly, 10 out of the 27 patients showed a dramatic improvement in severe anemia after two to ten months of therapy. Moreover, severe thrombocytopenia improved after two to four months of therapy in three out of these ten patients accompanied by a significant increase in megakaryocytes in bone marrow. Clonal cultures of bone marrow cells revealed a recovery in myeloid as well as erythroid precursors in most of these ten patients. In two patients who showed a trilineage response, mixed and megakaryocyte colony formations also recovered. These results suggest that long-term administration of rhG-CSF mobilizes myeloid, erythroid, megakaryocyte and multipotential progenitor cells and induces a multilineage response in some patients with AA.
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PMID:Multilineage response in aplastic anemia patients following long-term administration of filgrastim (recombinant human granulocyte colony stimulating factor). 750 23

Interferon-gamma (IFN-gamma), an immunoregulatory cytokine produced by activated T cells and natural killer cells in response to viral infection or other stimuli, is generally recognized as a suppressor of hematopoiesis. IFN-gamma inhibited in vitro colony formation by granulocyte-macrophage (GM), erythroid and multipotential progenitors. This cytokine exerted direct suppression on the proliferation process, but not on the commitment, of GM progenitors. The antiproliferative effects of IFN-gamma may, in part, result from the prolongation of the doubling time of GM progenitors. Clinically, IFN-gamma may play an important role in the pathogenesis of pancytopenia in aplastic anemia and in the hemophagocytic syndrome. However, as well as showing inhibitory effects, IFN-gamma increased the number of pure and mixed megakaryocyte colonies formed by post-5-fluorouracil treated bone marrow cells and, moreover, the addition of IFN-gamma to culture containing stem cell factor resulted in a synergistic effect on the development of both primitive hematopoietic progenitors and mature populations. These findings suggest that IFN-gamma has bifunctional activity in hematopoiesis.
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PMID:Hematopoietic progenitors and synergism of interferon-gamma and stem cell factor. 752 87

Effects of recombinant human interleukin (IL)-13 on in vitro haemopoiesis from non-adherent mononuclear cells (NAMC) or highly enriched CD34+ cells of human cord blood (CB) were studied. IL-13 significantly increased megakaryocyte (MK) colony formation from either NAMC or CD34+ cells cultured in a plasma clot system supplemented with aplastic anaemia serum (AAS) and phytohaemagglutinin-stimulated human peripheral blood leucocyte-conditioned medium (PHA-LCM) in a dose-dependent manner. Experiments using a modified plasma clot culture, in which normal AB serum and various cytokines were added to replace AAS and PHA-LCM, demonstrated an increased MK colony number in the presence of IL-13, especially in combination with IL-3. However, IL-13 had no stimulatory effect, but rather a slight inhibitory effect in some cases on granulocyte-macrophage (GM) colony formation in both plasma clot cultures. Furthermore, the growth of GM progenitor cells in a methylcellulose culture system in the presence of IL-3, GM-CSF, Epo, G-CSF or in combination was significantly inhibited by the addition of IL-13. On the other hand, high concentrations (100 ng/ml) of IL-13 were needed to cause a slight inhibition on the growth of BFU-E-derived colonies under the same methylcellulose culture. These results indicate that IL-13, alone and synergistically with the effect of IL-3, promotes MK colony formation, but it inhibits the growth of GM and erythroid progenitor cells in vitro.
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PMID:Differential effects of recombinant human interleukin-13 on the in vitro growth of human haemopoietic progenitor cells. 766 73

In this study we review our present understanding of the effect of stem cell factor (SCF) on the in vitro growth of hemopoietic progenitors from patients with acquired severe aplastic anemia (SAA). We have run three separate sets of experiments. First, we have tested the expression of receptor mRNAs for granulocyte-macrophage colony stimulating factor/interleukin 3 (GM-CSF/IL-3) and for c-kit protein on bone marrow (BM) cells from SAA patients. Molecular analysis revealed the presence of normal transcripts for alpha and beta chains of GM-CSF/IL-3 receptor and for c-kit protein by Northern blot analysis. Second, we have tested the in vitro response to SCF of BM cells derived from 11 SAA patients: SCF induced a significant enhancement of erythroid burst forming unit (BFU-E) growth (8 to 29, p = 0.01) and allowed the formation of granulocyte/erythroid/macrophage/megakaryocyte (GEMM) colonies which were not scored in baseline culture conditions (0 to 8, p = 0.01). Granulocyte-macrophage colony forming unit (CFU-GM) growth was also enhanced (4 to 20, p = 0.3). This was true for patients both at diagnosis and after antilymphocyte globulin (ALG) treatment. We concluded that SCF can promote the in vitro growth of hemopoietic progenitors in patients with acquired SAA. Third, we have tested the response to SCF of peripheral blood (PB) hemopoietic progenitors collected from patients receiving in vivo long-term treatment with granulocyte CSF (G-CSF). When PB cells were plated directly in the presence of GM-CSF there was no colony formation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro effect of stem cell factor on colony growth from acquired severe aplastic anemia. 769 24

A new culture and quantitation system has been established for growth of megakaryocyte-lineage cells from human progenitor cells. CD34+ progenitor cells were enriched from umbilical cord blood using an avidin-biotin immunoadsorption process. These cells were preincubated in bulk liquid culture for 3 to 4 days in the presence of the growth factors interleukin-3 (IL-3) and IL-6. The cells were then washed and seeded at 5000 cells/well in 96-well plates that contained a variety of test samples. The plates were incubated for 7 days, and the cells were then washed, transferred to ELISA plates, and fixed. Megakaryocyte growth was determined by an ELISA for the platelet glycoprotein (GP) IIb/IIIa, an abundant membrane protein found on cells committed to the megakaryocyte lineage. The growth factor IL-3 was found to produce a very strong signal in this assay. The addition of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-6, stem cell factor (SCF), or leukemia inhibitory factor (LIF) to low levels of IL-3 also stimulated megakaryocyte growth, as measured by IIb/IIIa expression. Plasma from patients with aplastic anemia was also stimulatory in this assay, and showed marked synergy with IL-3. This progenitor cell culture system, due to its judicious use of progenitor cells and an automated, 96-well quantitation method, allows for screening large numbers of test samples and multiple combinations and concentrations of growth factors.
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PMID:A new culture and quantitation system for megakaryocyte growth using cord blood CD34+ cells and the GPIIb/IIIa marker. 769 35

The effect of a low-molecular-weight heparin, faxiparin (Nadroparin), on murine megakaryocytopoiesis in vitro and in vivo was studied in comparison with unfractionated heparin. The addition of fraxiparin at 1-20 IU/ml into plasma clot cultures but not serum-free agar culture significantly enhanced MK colony growth. Furthermore, fraxiparin was found to potentiate the stimulating activity of aplastic anaemia serum (AAS) but not stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (Epo), on MK colony growth in vitro, and to neutralize the inhibitory effect of platelet factor 4 (PF4) in vitro and in vivo. Fraxiparin also acted synergistically with heparin cofactor II and antithrombin III to promote megakaryocyte colony formation. Intraperitoneal administration of fraxiparin twice daily for 4 d at 0.1-25 IU/injection increased in mice the level of blood platelet counts and the number of single MKs and CFU-MK in bone marrow. These data demonstrate that fraxiparin is able to positively regulate megakaryocytopoiesis.
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PMID:Fraxiparin, a low-molecular-weight heparin, stimulates megakaryocytopoiesis in vitro and in vivo in mice. 781 73

Megakaryocyte progenitor growth in 42 patients with myeloproliferative disorders (MPD), including 23 essential thrombocythaemia (ET), eight polycythaemia vera (PV), six chronic myelogenous leukaemia (CML) and five primary myelofibrosis (PMF), was studied in vitro using plasma clot assay and serum-free agar culture. Spontaneous megakaryocyte colonies (CFU-MK) were found in 34/40 (80%) blood and 14/18 (77.8%) bone marrow plasma clot cultures, and also observed in 27/35 (77.1%) blood and 10/18 (55.6%) bone marrow serum-free agar cultures. In the blood of 27 patients with MPD (15 ET, four PV, four CML and four PMF) and the bone marrow of 10 patients (five ET, four CML and one PV), spontaneous colony formation was observed in both plasma clot and serum-free agar cultures. However, spontaneous CFU-MK was only found in plasma clot culture, but not in agar culture in two blood (one ET and one CML) and four bone marrow cultures (one ET, two PV, one CML). The colony numbers were greatly increased in the presence of aplastic anaemia serum (AAS) under both conditions. In 17 patients (12 ET, two CML and three PV) with spontaneous megakaryocyte colonies, anti-cytokine antibody neutralizing experiments were carried out in blood cultures. Anti-IL3, anti-IL6 and anti-GM-CSF antibody, alone or in combination, at different concentrations (1, 5 and 10 micrograms/ml), were added into plasma clot or agar cultures without exogenous stimulating growth factors. The results showed that the numbers of spontaneous megakaryocyte colonies were not significantly decreased in the presence of these monoclonal antibodies in the cultures. The data indicated that the megakaryocyte progenitor growth in MPD under in vitro conditions was heterogenous, and independent of exogenous stimulatory factors in most patients and that optimal megakaryocyte colony development in MPD still requires exogenous growth factors. Three possibilities are discussed with regard to the phenomenon that the spontaneous colony formation was not decreased with the addition of anti-IL3, anti-IL6 and anti-GM-CSF antibodies.
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PMID:Spontaneous megakaryocyte colony formation in myeloproliferative disorders is not neutralizable by antibodies against IL3, IL6 and GM-CSF. 799 86

Granulocyte, macrophage colony stimulating factor (GM-CSF) and granulocyte--colony--stimulating factor (G-CSF) are two of the growing number of recognized cytokines involved in the regulation of hematopoiesis. The purification of these factors and the subsequent cloning of the DNAs which encode these proteins have led to their widespread clinical use in the setting up of therapy of disease-induced myelosuppression. GM-CSF has a broader spectrum of potential targets than G-CSF and promotes growth of progenitors of several myeloid lines and, to a lesser extent, of the megakaryocyte line. The pleiotropic effects of GM-CSF could therefore, theoretically, be an advantage compared with the more restricted activity of G-CSF. Its greatest potential use appears to be in the amelioration of neutropenia following myelosuppressive therapy. GM-CSF has demonstrated efficacy in decreasing the duration of neutropenia, decreasing the attendant infection, and enhancing the ability to deliver full doses of myelosuppressive therapy. GM-CSF can also reverse the neutropenia of myelodysplastic syndrome and aplastic anemia. It enhances recovery from bone marrow transplantation and thus reduce the attendant morbidity of this procedure. This hematopoietic growth factor may also enhance recruitment and harvest to peripheral stem cells. At clinically usefull dosages GM-CSF is generally well tolerated.
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PMID:[Biology and clinical applications of GM-CSF]. 806 93

The high-proliferative-potential colony-forming cell (HPP-CFC) has been shown to be clearly heterogeneous. Hierarchical subpopulations can be identified by analyzing the kinetics of cell regeneration and the specific cellular requirement for cytokines. In this study, a new type of HPP-CFC, termed high-proliferative potential mixed colony-forming unit-megakaryocyte (HPP-mCFU-MK), was detected in murine bone marrow cell cultures. The HPP-mCFU-MK was able to form macroscopic colonies that fit the criteria of the HPP-CFC colony but contained a number of megakaryocytes. Its growth was stimulated by either aplastic anemia serum (AAS) or a combination of three or more recombinant hematopoietic growth factors but was not inhibited by transforming growth factor-beta 1 (TGF-beta 1) and platelet factor 4 (PF4) in vitro. The recloning of the 12-day-old HPP-mCFU-MK colonies picked up from AAS-stimulated primary cultures caused secondary formation of HPP-CFC colonies. These data suggest that HPP-mCFC-MK is a new subset of stem cell characterized by its ability to produce directly a number of megakaryocytes in response to multifactor stimulation, to generate a secondary set of HPP-CFC in replating culture, and to be unaffected by TGF-beta 1 and PF4 treatment.
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PMID:Identification of a murine high-proliferative-potential colony-forming cell (HPP-CFC) capable of producing a number of megakaryocytes and replating for secondary HPP-CFCs in culture. 814 10

Because GM-CSF possesses burst-promoting activity (BPA) and megakaryocyte colony-stimulating activity (Meg-CSF) as well as stimulating activity on granulocyte-macrophage progenitors, and erythropoietin (Epo) has thrombopoietin-like activity, the combination therapy of GM-CSF and Epo seems to be more effective for stimulating erythropoiesis and thrombocytopoiesis in patients with pancytopenia. For this reason, the combination therapy of recombinant human GM-CSF (rhGM-CSF) and rhEpo was performed in two patients with refractory anemia (RA) and aplastic anemia (AA). Epo-unresponsive anemia was remarkably improved by adding rhGM-CSF to Epo and the effect lasted for 1 1/2 months in a patient with RA, but severe anemia occurred again immediately after the discontinuation of Epo. The neutralizing antibodies against GM-CSF were not demonstrated at the phase when anemia re-progressed in this patient. In a patient with AA, anemia and thrombocytopenia, which were refractory to previous administration of rhGM-CSF, responded to the combined administration of GM-CSF and Epo. Although the effects were maintained for 3 1/2 months, the anemia and thrombocytopenia became worse again after the administration of rhGM-CSF was changed from daily to every other day. These findings suggest the usefulness of combination therapy of GM-CSF and Epo for patients with pancytopenia.
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PMID:Combination therapy with rhGM-CSF and rhEpo for two patients with refractory anemia and aplastic anemia. 824 8


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