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 superoxide (O2-)-releasing capacity in response to N-formyl-methionyl-leucyl-phenylalanine (FMLP) and the priming effects of recombinant human granulocyte colony-stimulating factor (rhG-CSF) and granulocyte-macrophage colony-stimulating factor (rhGM-CSF) on FMLP-induced O2-release were investigated in neutrophils from 13 patients with aplastic anemia (AA). The O2(-)-releasing capacity of AA neutrophils (0.85 +/- 0.36 nmol/5 min/1 x 10(5) cells, n = 13) was significantly (p < 0.01) increased as compared with that of normal neutrophils (0.24 +/- 0.12 nmol/5 min/1 x 10(5) cells, n = 17). There was no close relationship between the O2(-)-releasing capacity and the peripheral blood neutrophil count or the plasma concentration of C-reactive protein. The plasma concentrations of G-CSF and GM-CSF were not elevated to the detectable levels (< 0.1 ng/ml and < 0.2 ng/ml, respectively) in all patients tested. FMLP-induced O2(-)-release was further enhanced by pretreatment of cells with rhG-CSF or rhGM-CSF for 10 min at 37 degrees C, except that no significant priming by rhG-CSF was observed in five patients. The priming effect of rhGM-CSF was consistently greater than that of rhG-CSF in all patients. The i.v. administration of rhGM-CSF (6 micrograms/kg body weight/day) to one patient resulted in an increase in neutrophil O2(-)-release stimulated by FMLP. These findings indicate that neutrophils from AA patients are already primed in vivo for enhanced release of O2- and that these neutrophil functions are further potentiated by rhG-CSF or rhGM-CSF.
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PMID:Increased respiratory burst activity of neutrophils in patients with aplastic anemia: effects of granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor. 128 85

We have studied stromal cell function in naive or interleukin-1 (IL-1)-stimulated (100 pg/ml) long-term marrow cultures (LTC) from 12 normal donors and 21 patients with severe aplastic anemia (AA). Conditioned media (CM) from normal LTC contained levels of erythroid burst-promoting activity (BPA) and granulocyte/macrophage (GM) colony-stimulating activity (CSA) comparable to those previously described (Migliaccio et al., [1990] Blood, 75:305-312). The addition of IL-1 to these cultures increased the level of CSA and, specifically, of granulocyte colony-stimulating factor (G-CSF) released. Anti-GM-CSF antibody neutralized BPA and CSA in normal naive LTC CM but only the CSA in the CM from IL-1-stimulated LTC. Since the concentrations of GM-CSF, as detected with a specific immunoassay, did not increase after IL-1 treatment, these data suggest that IL-1-stimulated cultures contain an unidentified growth factor having BPA. CM from AA stromal cells contained levels of CSA comparable to those observed in normal stromal cell CM but had significantly lower levels of BPA. Neither anti-GM-CSF nor anti-IL-3 antibodies neutralized the BPA in AA stromal cell CM. This activity may be related to that found in the CM of IL-1-treated normal stromal cells. In nearly 50% of stromal cell cultures of AA patients, addition of IL-1 failed to increase the BPA, CSA, or G-CSF. The presence of an inhibitor in naive or IL-1-treated AA stromal cell CM was excluded by adding the CM to IL-3-stimulated cultures. These findings suggest that G-CSF and GM-CSF genes are differentially regulated in the marrow microenvironment. Furthermore, a marrow microenvironment, deficient in BPA production and, in some cases, unresponsive to IL-1 could contribute to marrow failure in some patients with AA.
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PMID:Production of granulocyte colony-stimulating factor and granulocyte/macrophage-colony-stimulating factor after interleukin-1 stimulation of marrow stromal cell cultures from normal or aplastic anemia donors. 137 99

The aim of this study was to evaluate the effect of stem cell factor (SCF) on the in vitro growth of bone marrow hematopoietic progenitors from patients with acquired severe aplastic anemia (AA) or Fanconi's anemia (FA). For this purpose, we studied 11 patients with acquired AA (5 at diagnosis, 6 after ALG treatment), 12 patients with FA, and nine normal controls. Bone marrow cells were plated in vitro for colony-forming unit granulocyte-macrophage (CFU-GM) (in the presence of granulocyte-macrophage colony-stimulating factor [GM-CSF]), and for burst-forming unit-erythroid (BFU-E) and CFU-granulocyte, erythroid, monocyte, megakaryocyte (CFU-GEMM) colonies (in the presence of erythropoietin and interleukin-3 [IL-3]), with or without 20 ng/mL of SCF. In normal controls, SCF enhanced the growth of CFU-GM colonies from 103 to 263 (median), of BFU-E from 168 to 352, and of GEMM colonies from 6 to 38/10(5) cells plated. In patients with acquired AA, SCF induced a significant enhancement of BFU-E growth (8 to 29; P = .01) and allowed the formation of GEMM colonies that were not scored in baseline culture conditions (0 to 8; P = .01). CFU-GM growth was enhanced (4 to 20), but not significantly (P = .3). This was true both for patients at diagnosis and after antilymphocyte globulin treatment. By contrast, 10 of 12 FA patients grew no CFU-GM, BFU-E, or CFU-GEMM colonies, with or without SCF. In two FA patients (one transfusion-dependent and one transfusion-independent), an enhancement of CFU-GM and/or BFU-E was observed. The lack of response of hematopoietic progenitor cells from FA patients to GM-CSF+SCF or IL-3+SCF was not dependent on a defective expression of cytokine receptor messenger RNAs. Northern blot analysis showed in marrow cells from acquired AA and FA patients the presence of normal transcripts for alpha- and beta-chains of GM-CSF/IL-3 receptor and for c-kit protein. In conclusion, SCF promotes the in vitro growth of hematopoietic progenitors in patients with acquired AA, but not in patients with FA, pointing out the intrinsic nature of the defect in the latter disorder.
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PMID:Effect of stem cell factor on colony growth from acquired and constitutional (Fanconi) aplastic anemia. 137 17

In this study we have analyzed the activity of Cyclosporin A (CsA) on the "in vitro" production of TNF and IL-3/GM-CSF as a preliminary basis for explaining the successful use of CsA in aplastic patients. Thus, 73 T cell clones, obtained by a limiting dilution technique from the peripheral blood and bone marrow of 3 patients with severe aplastic anemia (SAA), were studied for TNF and IL-3/GM-CSF production as induced by stimulation with 1% PHA plus 1 ng/ml TPA. Lymphokines obtained in this manner were then tested by biological assays. Twelve out of the initial 73 T cell clones were selected for the production of a large quantity of IL-3/GM-CSF and/or TNF. With these clones we studied the ability of CsA to inhibit TNF and IL-3/GM-CSF production, which was stimulated with specific monoclonal antibodies directed against the CD2 and CD3 surface antigens. TNF and IL-3/GM-CSF production displayed a different sensitivity to CsA inhibition. In fact, at 400 ng/ml CsA a residual production of IL-3/GM-CSF was present in all clones tested (CD3: 21.8% and CD2: 14.4% of the maximal IL-3/GM-CSF activity), while secretion of TNF was virtually abrogated at 100 ng/ml. Moreover, the mean ID50 for TNF production was significantly lower than that of IL-3/GM-CSF (CD2: p = 0.028, CD3: p = 0.01). Using specific anti-IL-3 and anti-GM-CSF monoclonal antibodies, we showed that only GM-CSF, and not IL-3, was resistant to CsA inhibition. In conclusion, these results may represent a possible explanation of the successful use of CsA in the treatment of some patients with SAA.
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PMID:Effect of cyclosporin A on T cell clones from severe aplastic anemia: differential sensitivity of TNF and GM-CSF production. 142 30

Subcutaneous administration of recombinant human Interleukin-1 beta (IL-1 beta) in a dose of 1-3 x 10(4) U/day for 14 to 72 days resulted in an increase in circulating granulocytes and bone marrow monocytes in all the 4 patients examined. Circulating platelet count was also increased in two of four patients with myelodysplastic syndrome (MDS) and aplastic anemia (AA). Bone marrow examination revealed an increase in megakaryocyte count in these patients, whereas the percentage of blast was not changed. An increase in blood platelet count was accompanied by an increase in serum GM-CSF in a patient with AA, whereas serum IL-6 level was not changed throughout the treatment with IL-1 beta. These findings suggest that IL-1 beta may be useful for the treatment of a proportion of patients with MDS and AA who are associated with thrombocytopenia.
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PMID:[Effect of subcutaneous administration of interleukin-1 beta on blood platelet count and serum GM-CSF in patients with myelodysplastic syndrome and aplastic anemia]. 143 38

The in vivo response to recombinant human granulocyte-monocyte colony-stimulating factor (rHu GM-CSF) in facilitating the reconstitution of granulomonopoiesis was evaluated in a patient with Graves' disease who developed severe aplastic anemia during methimazole therapy. After 10 days of treatment with rHu GM-CSF, the neutrophil and monocyte counts rose to 1.65 x 10(9)/l and 0.41 x 10(9)/l, respectively. However, the patient was still dependent on erythrocyte and platelet transfusions. Two days after rHu GM-CSF withdrawal, the neutrophil count dropped off to 0.41 x 10(9)/l.rHu GM-CSF was reinitiated for 2 days along with glucocorticosteroids. With this combined therapeutic approach, the neutrophil count returned to normal and remained stable, and both Hb and platelet values began to improve. It is concluded that the combination of rHu GM-CSF and glucocorticosteroids can be used as a therapeutic option that may lead to beneficial results in drug-induced aplastic anemia.
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PMID:Treatment of methimazole-induced severe aplastic anemia with recombinant human granulocyte-monocyte colony-stimulating factor and glucocorticosteroids. 164 96

The treatment of severe aplastic anemia has been modified recently by the demonstration that Cyclosporine A is active alone or in combination leading to more than 50% response rate. Combination or sequential treatments with ATG seem to be better than such drug separately but this must be studied in randomized studies. Long term follow-up is necessary to assess the rate of malignant transformation. Growth factors have been recently introduced. G or GM-CSF seem to be active. IL-3 has not been proven to be effective in very small non randomized study. Allogeneic bone marrow transplantation is the best treatment with a matched related donor, progress must be achieved in methods of conditioning and GVH prophylaxis when a matched unrelated donor is used.
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PMID:Recent treatments of aplastic anemia. The International Group on SAA. 181 8

The aim of this study was to test whether large amounts of recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) are capable of promoting the growth of hemopoietic progenitors from patients with marrow failure. For this purpose 0.1, 100, 1000, 10,000 and 20,000 ng/ml of rhGM-CSF were added to 10(5) light-density (adherent cell-depleted) bone marrow cells from 9 normal controls and from 52 patients with aplastic anemia, 25 cases of which were transfusion-dependent (Tx-D) aplastic anemia (AA) and 27 of which were transfusion-independent (Tx-I) aplastic anemia (AA). A dose-dependent increase of granulocyte-macrophage colony-forming units (CFU-GM) was observed in healthy donors, from 81 to 247 colonies at 0.1 and 1000 ng/ml of rhGM-CSF, with a plateau thereafter. Tx-I AA patients showed the best increase of CFU-GM in response to colony-stimulating factor, from 0.1 to 32.7 mean colonies at 0.1 and 20,000 ng/ml of rhGM-CSF, and the increment was greater when compared to controls. The ratio of CFU-GM grown from these patients and controls was 1:810 at 0.1 ng/ml of rhGM-CSF and 1:7.9 at 20,000 ng/ml. Eleven patients were studied at diagnosis; there was no in vitro response to rhGM-CSF (0 and 1.8 mean colonies/10(5) cells at 0.1 and 10,000 ng/ml). Overall, Tx-D AA patients showed minimal increments of CFU-GM growth at very high doses of rhGM-CSF. Two suggestions come from this study: 1) maturation of CFU-GM from recovering AA patients appears to require larger doses of GM-CSF than normal controls, and 2) very high doses of rhGM-CSF have little or no effect on CFU-GM growth in AA patients. This may be relevant for clinical studies designed to improve hemopoiesis in patients with marrow failure.
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PMID:Response of CFU-GM to increasing doses of rhGM-CSF in patients with aplastic anemia. 186 97

Colony stimulating factors and interleukins regulate proliferation, differentiation, and functional activation of hematopoietic cells of multiple lineages. These hematopoietic growth factors are proving effective in vivo in stimulation of granulopoiesis in clinical situations associated with myelosuppression. G-CSF and GM-CSF promote accelerated granulocyte recovery following chemotherapy, or allogeneic or autologous bone marrow transplantation, in patients with cancer. In congenital defects of granulocyte production or in acquired disorders such as idiopathic neutropenia or aplastic anemia, CSF administration can lead to recovery of functioning granulocytes. This has resulted in a reduction in the morbidity and mortality associated with these diseases and now permits both a dose and a schedule intensification of chemotherapy. In myeloid leukemia and myelodysplastic syndromes, CSF treatment, particularly G-CSF, has proved effective for certain patients in improving neutrophil, platelet, and occasionally red cell production while reducing blast cells. The recombinant growth factors are generally well tolerated with few limiting toxicities at dose levels that effectively stimulate hematopoiesis.
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PMID:The clinical use of colony stimulating factors. 191 Jun 75

Serum albumin, cholinesterase, and cholesterol were measured in ten patients with aplastic anemia and eight with myelodysplastic syndrome who received the administration of recombinant human GM-CSF. Serum albumin, cholinesterase, and cholesterol were significantly lowered by the administration of GM-CSF and recovered after the cessation of GM-CSF. These data suggest that GM-CSF impairs the biosynthesis of liver cells and that cholesterol-lowering activity of GM-CSF, which is previously reported, is due to the impairment of liver biosynthesis by GM-CSF.
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PMID:GM-CSF-mediated impairment of liver to synthesize albumin, cholinesterase, and cholesterol. 199 59


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