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)

Cyclosporine (CyA) therapy has been shown to be effective in some patients with aplastic anemia. In an attempt to characterize aplastic patients likely to benefit from CyA therapy, we examined bone marrow mononuclear cells (BMMC) obtained before therapy from 23 patients with aplastic anemia, who were treated with CyA alone. Expression of four myelosuppressive cytokines, including tumor necrosis factor (TNF), lymphotoxin, macrophage inflammatory protein-1 alpha (MIP-1 alpha), and interferon-gamma (IFN-gamma) was examined using polymerase chain reaction (PCR)-assisted messenger RNA (mRNA) amplification. mRNA for TNF, lymphotoxin, and MIP-1 alpha was readily detectable at variable levels in BMMC from normal and transfused controls as well as in BMMC from aplastic patients. In contrast, IFN-gamma mRNA was only demonstrable in BMMC from some patients with aplastic anemia, irrespective of a history of transfusions. Of 13 patients who responded to CyA therapy and achieved transfusion-independence, IFN-gamma mRNA was detected in 12 patients, whereas the mRNA was only detectable in 3 of 10 patients refractory to CyA therapy (P = .003, Fisher's exact test). Follow-up examination of BMMC obtained from seven CyA-responding patients after hematologic remission showed disappearance of IFN-gamma mRNA in four patients. These results suggest that detection of IFN-gamma gene expression in pretreatment BMMC from aplastic patients using PCR may be helpful in predicting a good response to CyA therapy.
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PMID:Interferon-gamma gene expression in unstimulated bone marrow mononuclear cells predicts a good response to cyclosporine therapy in aplastic anemia. 158 5

The aim of the present study was to compare the response of bone marrow (BM) lymphocytes from patients with aplastic anemia (AA) or normal controls to increasing doses of antilymphocyte globulin (ALG) or phytohemagglutinin (PHA). For this purpose BM T-enriched cells from 11 AA patients and 9 normal individuals were incubated with ALG (0-1000 micrograms/ml) or PHA (0%-10%) for 1 day, and the supernatants were tested for suppression/enhancement of granulocyte-macrophage colony-forming unit (CFU-GM) growth and for release of granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) assayed with the enzyme-amplified sensitivity immunoassay (EASI). The production of colony-stimulating activity (CSA) by T cells primed with ALG and tested in the absence of exogenous GM-CSF correlated with the dose of ALG in priming cultures up to 14% EG (100% EG = CFU-GM growth with 30 ng/ml of GM-CSF). The amount of GM-CSF in the supernatants paralleled their capacity to sustain CFU-GM growth (up to 3.5 ng/ml of GM-CSF). Production of CSA or GM-CSF from T cells primed with PHA was significantly lower. Supernatants of PHA-primed T cells, when added to normal BM cells in the presence of exogenous GM-CSF, produced a dose-dependent inhibition of CFU-GM growth (down to 13% +/- 10% EG). The same supernatants contained detectable amounts of IFN-gamma and TNF-alpha (21 +/- 6.7 IU/ml and 4.6 +/- 2.9 ng/ml, respectively). IFN-gamma production from severe AA (SAA) T cells in response to PHA was significantly superior to the IFN-gamma production from normal T cells (21 +/- 6.7 IU/ml vs 9.5 +/- 7.1 IU/ml, p = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vitro response of T cells from aplastic anemia patients to antilymphocyte globulin and phytohemagglutinin: colony-stimulating activity and lymphokine production. 190 92

The activity of tumor necrosis factor-alpha (TNF-alpha) in the supernatant of cultured peripheral blood mononuclear cells (PBMC) was measured in patients with aplastic anemia. It was significantly higher in patients with aplastic anemia than in normal controls, both when PBMC were unstimulated or when they were stimulated with PHA. Results from aplastic anemia patients were also significantly higher than patients who had received allogeneic bone marrow transplants. In aplastic anemia patients, the TNF-alpha value produced by PBMC upon stimulation and the platelet count were inversely correlated, as well those patients who had high TNF-alpha values tended to have lower hemoglobin and leukocyte values although this was not significant statistically. These results suggest that the increased production of TNF-alpha by PBMC plays a role in the severe suppression of hematopoiesis in aplastic anemia.
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PMID:Increased production of tumor necrosis factor-alpha by peripheral blood mononuclear cells in the patients with aplastic anemia. 206 66

Interferon-gamma (IFN-gamma) and tumor necrosis factor (TNF) are lymphokines with a potent hematopoietic progenitor cell suppressive capacity. In untreated and immunosuppressed patients with severe aplastic anemia (SAA) and in control individuals we measured (a) serum levels of IFN-gamma and TNF and its production by peripheral blood mononuclear cells (PBMNC); (b) serum levels of neopterin, a product that reflects endogenous IFN production; (c) resting and activated lymphocyte subpopulations; and (d) serum levels of soluble interleukin-2 receptor (IL-2R). Serum levels of IFN and TNF did not differ significantly in untreated and treated SAA patients and control individuals. Spontaneous and phytohemagglutinin-induced production of IFN and TNF by PBMNC, however, were highly increased in both untreated and treated SAA patients. Increased and decreased neopterin serum levels in untreated and treated SAA patients, respectively, suggest modulation of endogenous lymphokine release subsequent to immunosuppression. HLA-DR+ antigen was mainly expressed by CD8 T cells. Circulating numbers of activated (CD4 and CD8) T cells and serum levels of IL-2R were not increased in both untreated and treated SAA patients. The proportion of HLA-DR+ T cells in the PBMNC of untreated SAA patients correlated with the extent of lectin-induced IFN production. Although we were unable to confirm previous reports in SAA on (a) detectable IFN in blood and bone marrow serum, (b) improvement of stem cell growth upon neutralization of endogenous IFN, (c) absolutely increased numbers of circulating activated T cells, and (d) normalization of these abnormalities subsequent to successful immunosuppression, our data clearly support previous reports on abnormal lymphokine production in severe aplastic anemia. Our failure to relate this phenomenon to the severity of disease states, however, further raises doubts on the pathogenetic significance of lymphokine overproduction in SAA.
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PMID:Further evidence for lymphokine overproduction in severe aplastic anemia. 249 36

We studied spontaneous cytokine production by peripheral blood mononuclear cells (PBMC) obtained from 14 patients with aplastic anemia (AA) and 28 various myelodysplastic syndromes (MDS). The levels of interleukin-6, interleukin-1 beta, and tumor necrosis factor-alpha in cultured PBMC were measured by ELISA. The average levels of these cytokines were higher in AA or in refractory anemia (RA) than in RA with excess of blasts (RAEB) or in RAEB in transformation (RAEB-T). Marked cytokine overproduction was observed in RA as well as in AA. High cytokine levels were observed in hypocellularity and low blast cell counts in the bone marrow. These results may suggest that the increase of cytokines may be a reactive response in hypocellular bone marrow.
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PMID:Spontaneous cytokine overproduction by peripheral blood mononuclear cells from patients with myelodysplastic syndromes and aplastic anemia. 756 74

Plasma levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) were determined in healthy individuals and patients with aplastic anemia (ApAn). IFN-gamma was not detected in normal peripheral blood plasma (PBP) or bone marrow plasma (BMP) and was present in PBP from only 2 of 22 patients and in BMP from 1 of 14 patients and the levels were low (< 1.5 U/ml). Elevated levels of TNF-alpha were present in BMP and PBP from patients but not in control (healthy donor) PBP and BMP. Eleven of twenty-four patients had elevated levels of TNF-alpha in their PBP and 6 of 13 patients had detectable levels of TNF-alpha in their BMP. Only one of the 14 healthy control donors had detectable TNF-alpha and the level was very low (7 pg/ml), while 13 of the 27 ApAn patients had detectable TNF-alpha (P = .009, chi-square test). Not surprisingly, the centers of the distributions of TNF-alpha concentrations of the controls and ApAn patients differed significantly (P < .017 for control and patient PBP and P < .056 for control and patient BMP, Wilcoxon rank-sum test). Spontaneous production of IFN-gamma and TNF-alpha by cultured bone marrow mononuclear cells was observed in four of seven patients but not in the six healthy controls (P = 0.026). Spontaneous production of IFN-gamma and TNF-alpha by cultured peripheral blood mononuclear cells from patients and controls was however similar. Phytohemagglutinin (PHA)-induced production of IFN-gamma and TNF-alpha by cultured mononuclear cells did not differ significantly between ApAn patients and normal controls. The significance of overproduction of TNF-alpha in the pathophysiology of ApAn is discussed.
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PMID:Detection of tumor necrosis factor-alpha in bone marrow plasma and peripheral blood plasma from patients with aplastic anemia. 825 9

Erythroid aplasia is induced in cats by feline leukemia virus (FeLV) of subgroup C but not by FeLV of subgroup A. In an investigation of the role of macrophages in FeLV-C-induced diseases, the concentrations of FeLV and tumor necrosis factor-alpha (TNF-alpha) were compared between feline peritoneal macrophages incubated with FeLV of subgroup A or C. FeLV of both subgroups infected macrophages, but expression of FeLV-C was 21-fold higher than FeLV-A in peritoneal macrophages (P = .004). The supernatants of FeLV-C-inoculated macrophage cultures contained significantly higher levels of TNF-alpha (70 +/- 14 U/mL) at 72 hours postincubation compared with FeLV-A-inoculated (38 +/- 8 U/mL) and uninoculated (31 +/- 8 U/mL) cultures. Moreover, a positive correlation was shown between cell-associated FeLV surface glycoprotein gp70 and TNF-alpha expression in FeLV-C-infected macrophages by immunofluorescence (r = .6; P = .001), measured with a computer-assisted, laser-based digital imaging system. The addition of TNF-alpha to a uniform population of FeLV-infected cells (feline embryonic fibroblasts) caused an enhancement of viral expression (P < .05). These results indicate that FeLV-C has tropism for macrophages, FeLV expression is positively correlated with TNF-alpha expression in macrophages, and TNF-alpha enhances FeLV replication in fibroblasts. We suggest that FeLV-C infection of macrophages and secretion of TNF-alpha may be important in hematopoietic suppression in FeLV-C-infected cats.
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PMID:Macrophage tropism of feline leukemia virus (FeLV) of subgroup-C and increased production of tumor necrosis factor-alpha by FeLV-infected macrophages. 838 34

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and to determine their effect on the clonal growth of normal bone marrow (BM) cells. Twenty-one patients with AA and 11 normal controls were enrolled in this study. Medium conditioned by PBMNC of AA patients in the presence of lipopolysaccharide (LPS) was found to be suppressive to the colony growth of normal BM cells. Thus, we further determined the presence in the PBMNC-conditioned medium (CM) of both inhibitory cytokines: macrophage inflammatory protein-1 alpha (MIP-1 alpha), tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta 2 (TGF-beta 2), and interferon-gamma (IFN-gamma), and stimulatory cytokines: interleukin-3 (IL-3) and stem cell factor (SCF). Spontaneous production of MIP-1 alpha was higher in the AA patients than the normal controls (1887 +/- 174 pg/ml vs 1643 +/- 93 pg/ml), but the difference was not significant. After LPS stimulation, the production of MIP-1 alpha was markedly increased in the AA patients, and its level was significantly higher than that of the normal controls (2360 +/- 149 pg/ml vs 1517 +/- 92 pg/ml, p = 0.0022). The level of TNF alpha was also higher in the AA patients. However, IFN-gamma, TGF-beta 2, SCF, and IL-3 were not detectable in the PBMNC-CM of either AA patients or normals. The myelopoietic suppressing effect of AA-PBMNC-CM from each AA patient was significantly blocked by pretreatment with anti-TNF-alpha, resulting in a colony-forming enhancement of 174% +/- 12%. A similar effect was noted in six of 11 AA patients by pretreatment with anti-MIP-1 alpha. We conclude that TNF alpha and MIP-1 alpha can be overproduced by the PBMNC of some AA patients, which may play a role in the progression of AA.
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PMID:Overproduction of inhibitory hematopoietic cytokines by lipopolysaccharide-activated peripheral blood mononuclear cells in patients with aplastic anemia. 853 59

The aim of this study was to measure the level of cytokines produced by peripheral blood mononuclear cells (PBMNC) in patients with aplastic anemia (AA) and determine their effect on normal bone marrow (BM) colony growth. Thirty-five patients with AA and 21 normal controls were enrolled in the study. Medium conditioned by PBMNC of AA patients in the presence of phytohemagglutinin (PHA) was found to be suppressive to the clonal growth of normal BM cells. Thus, we further determined the presence in the PBMNC conditioned medium (CM) of inhibitory cytokines (macrophage inflammatory protein-1 alpha [MIP-1 alpha], transforming growth factor-beta 2 [TGF-beta 2], interferon-gamma [IFN-gamma], and tumor necrosis factor-alpha [TNF-alpha]) and stimulatory cytokines (granulocyte-macrophage colony-stimulatory factor [GM-CSF], interleukin-3 [IL-3], and stem cell factor [SCF]). The results show no significant difference between AA patients and normal controls in the spontaneous production of all cytokines by PBMNC. After PHA stimulation, the production of MIP-1 alpha, IFN-gamma, TNF-alpha, and GM-CSF significantly increased in the cultures of AA patients (p = 0.0009, 0.0002, 0.0022, and 0.0156, respectively). However, both TGF-beta 2 and SCF were undetectable in most of the tested samples. IL-3 was measured in the conditioned medium only after PHA stimulation, but without significant difference between the two groups (p = 0.67). Furthermore, the myelopoietic suppressing effect of AA-PBMNC CM could be significantly blocked by pretreatment with specific antibodies to the corresponding inhibitory cytokines (MIP-1 alpha, IFN-gamma, and TNF-alpha). After antibody neutralization, an apparent change occurred in the clonal growth of normal BM cells incubated with AA-PBMNC CM, resulting in colony enhancement of 205, 131, and 237% by anti-MIP-1 alpha, anti-IFN-gamma, and anti-TNF-alpha, respectively. These results suggest that overproduction of inhibitory cytokines, rather than underproduction of stimulating cytokines, may play a role in the progression of at least some patients with AA.
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PMID:Production of hematopoietic regulatory cytokines by peripheral blood mononuclear cells in patients with aplastic anemia. 853 89

A 39-year-old patient with severe aplastic anemia (AA), resistant to therapy, received recombinant human IL-3 (rhIL-3) on a phase I/II trial. During treatment she developed disseminated skin lesions, suggestive of vasculitis, and severe progressive peripheral neuropathy culminating in complete paralysis. She died 25 days after beginning treatment from profuse bleeding. On autopsy, evidence of vascular leaks with widespread bleeding and extensive hemorrhagic involvement of peripheral nerves was found. An additional feature was massive reactive erythrophagocytosis in lymph nodes, spleen and bone marrow. The coincidence between rhIL-3 administration and the dramatic events suggest a causal relation. As a possible pathogenic mechanism, an rhIL-3 induced excessive stimulation of macrophages and production of secondary cytokines such as tumor necrosis factor (TNF) is suggested. TNF is considered as a major factor in the development of both a vascular leak and reactive erythrophagocytosis. This case report can be regarded as an example of the possible unusual pathologic phenomena we may expect to see in the near future with increasing use of growth factors.
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PMID:Fatal vascular leak syndrome with extensive hemorrhage, peripheral neuropathy and reactive erythrophagocytosis: an unusual complication of recombinant IL-3 therapy. 862 77


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