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 inhibitory activity of T cells on autologous erythroid colony-forming units (CFU-E) (T cell inhibitory activity) in patients with aplastic anaemia (AA) was investigated. In 11 (32.4%) out of 34 AA cases, T cell inhibition on autologous CFU-E growth was greater than that in normal individuals. In order to evaluate the mechanism of this inhibitory activity, T cell surface markers, interferon (IFN) production in peripheral blood mononuclear cell (PBMNC) liquid culture, and cytokine levels such as IFN and tumour necrosis factor-alpha (TNF-alpha) in CFU-E clot cocultured with T cells, were measured in a portion of the patients. In five patients investigated for IFN production in PBMNC liquid culture, all produced statistically more IFN activity than normal individuals under phytohaemagglutinin (PHA-P) stimulation (P less than 0.01) with no relation to T cell inhibitory activity. In only one patient whose T cells displayed increased CD8 and HLA-DR antigen (CD8+HLA-DR+) and inhibitory activity, a significant amount of IFN-gamma was observed in CFU-E clot cocultured with T cells, and the addition of anti-IFN-gamma antibody to the coculture resulted in recovered CFU-E colony growth. These results suggest that IFN-gamma production by T cells may explain, at least in part, the pathogenesis of haematopoietic defects in AA. In other patients however, T cell inhibitory activity neither correlated to the T cell subpopulations (CD4+/CD8+, CD8+HLA-DR+), IFN production in PBMNC liquid culture, nor to IFN and TNF-alpha levels in CFU-E clot culture. The roles played by cytokines other than IFN and TNF-alpha on haematopoietic precursor cells require further evaluation in a larger sample of patients with AA.
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PMID:T cell-mediated inhibition of erythropoiesis in aplastic anaemia: the possible role of IFN-gamma and TNF-alpha. 190 11

Cyclosporin A is used to prevent graft-versus-host disease (GvHD) following bone marrow transplantation (BMT) and it has been implicated in reducing the time to engraftment for leukaemia and aplastic anaemia patients. To evaluate the effect of cyclosporin A on engraftment, the proliferative capacity of bone marrow progenitors (CFU-E, CFU-F and CFU-C) was assessed both in vitro and following treatment with cyclosporin A over a 9-week period using an animal model. Cyclosporin had a differential effect on the haemopoietic progenitors, with the myeloid series unaffected at therapeutic concentrations. Both erythroid and stromal progenitors were significantly inhibited at similar concentrations. The mechanism by which cyclosporin A enhances engraftment remains unclear; however, it is not mediated by enhancing any of the haemopoietic progenitors.
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PMID:Inhibitory effect of cyclosporin A on erythroid and stromal colonies. 195 87

Twenty children (aged 1 to 17 years) with severe or moderate aplastic anemia were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) at a dose of 400 micrograms/m2 per day administered as a 30-minute intravenous (IV) infusion daily for 2 weeks. This treatment increased the neutrophil counts (2.7- to 28.0-fold) in 12 of the 20 patients. Increasing doses (800 or 1,200 micrograms/m2 per day) were administered to five patients who had not responded to the initial dose, and three showed an increase in neutrophil count. Differential counts of bone marrow (BM) aspirates showed an increase in the myeloid/erythroid ratio. The response was transient, however, and the neutrophil count returned to baseline within 2 to 10 days of discontinuing treatment. No severe toxicity attributable to rhG-CSF was observed. The results suggest that this agent is effective in stimulating granulopoiesis in children with aplastic anemia. Our study also indicates that rhG-CSF will be particularly useful in managing patients with aplastic anemia complicated by bacterial or fungal infection.
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PMID:Treatment of aplastic anemia in children with recombinant human granulocyte colony-stimulating factor. 199 1

Ten patients with paroxysmal nocturnal hemoglobinuria were studied. The diagnosis was made on the basis of hemolytic anemia, a positive Ham test and hemosiderinuria. Six patients had primary paroxysmal nocturnal hemoglobinuria evolved from aplastic anemia. These four patients also had a milder form of the disease, Over long periods of the follow-up, large variations of hemoglobin values and red blood cell counts were observed. Both absolute and percent reticulocyte counts were increased. Erythroblast counts in the bone marrow were 3-5 times higher than normal. Reticulocyte counts in the bone marrow were 3-5 times higher than normal. Reticulocyte counts showed wide variations but substantially smaller than those in autoimmune hemolytic anemias. Serum iron was either normal or increased, while the bone marrow iron store was high or low. However, the finding of urinary hemosiderin in all cases spoke against depletion of iron stores. The red blood cell life span was moderately shortened. Kinetic studies with 59Fe showed a high red blood cell iron incorporation, while the curves frequently had irregular shapes (broken curve) or an early, abrupt fall. Studies of late erythroid progenitors (CFU-E) indicated that this compartment was preserved. Even after long observation periods was no stem cell pool depletion due to an increased red blood cell demand observed.
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PMID:Erythropoiesis in paroxysmal nocturnal hemoglobinuria. 207 18

The morphologic changes in the bone marrow of eight patients with refractory aplastic anemia who received 4 or more weeks of granulocyte macrophage-colony-stimulating factor (GM-CSF) are described. All eight patients demonstrated a continuous rise in the absolute number of neutrophils, eosinophils, and monocytes over the first four weeks of therapy. Bone marrow examination revealed a progressive increase in bone marrow cellularity in all patients except one. An increase in myeloid: erythroid ratio was seen with progressive maturation of granulocytic cells. Neutrophilic and eosinophilic myelocytes were the most prominent cells. The percentage of myeloblasts and promyelocytes did not increase significantly, and the proportions of postmitotic granulocytic cells did not change either. No significant morphologic changes were noted in the basophilic, erythroid, and megakaryocytic series. The most prominent topographic observation in the bone marrow during GM-CSF therapy was the frequent clustering of myeloid cells close to the bone trabeculae. The periosteal localization of myeloid precursors may reflect a higher concentration of stem cells and/or stromal cells in the bone marrow adjacent to the bone trabeculae or a higher concentration of growth factors. Careful morphologic examination of bone marrow in CSF clinical trials will provide useful information regarding the in vivo effects of these growth factors, and will aid in the development of a rational approach to combining them for therapy.
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PMID:Bone marrow changes in patients with refractory aplastic anemia treated by recombinant GM-CSF. 219 66

The osteoclast derives from the haemopoietic stem cell but its relationship with the other progeny of the haemopoietic system is unknown. Osteoclast numbers were assessed in patients with aplastic anaemia and were found not to be depleted compared with a control population. This suggests that the osteoclast may develop along a separate lineage which is independent of the colony forming unit granulocyte, erythroid cell, monocyte, and megakaryocyte (CFU GEMM).
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PMID:The osteoclast, which derives from a haemopoietic stem cell, is not depleted in aplastic anaemia. 226 64

The presence of interferon (IFN) in normal bone marrow and its abnormal production in aplastic anemia suggest that IFN may have normal regulatory roles and implicates them in the pathophysiology of bone marrow failure. We studied the effects of recombinant IFN (r-IFN) on hematopoietic colony formation in methylcellulose cultures of human bone marrow. Both recombinant IFN-gamma (r-IFN-gamma) and recombinant IFN-alpha (r-IFN-alpha) were potent suppressors of myeloid (CFU-C-derived) colony formation, with 50% inhibition occurring at 291 u/ml for r-IFN-gamma and 275 U/ml for r-IFN-alpha. Small amounts of r-IFN-gamma acted synergistically with r-IFN-alpha; as little as 5 U/ml of r-IFN-gamma increased inhibition of CFU-C-derived colony formation by r-IFN-alpha over threefold. Conversely, small amounts of r-IFN-alpha did not affect inhibition by r-IFN-gamma. Inhibition by r-IFN was highly dependent on culture conditions: reduction of the fetal calf serum concentration from 30% to 20%, a change that did not alter the plating efficiency of control cultures, significantly enhanced the action of r-IFN-gamma. Competition between positive hematopoietic factors and r-IFN was further demonstrated as increasing amounts of human placenta-conditioned media, used as a source of colony-stimulating activity, also partially blocked r-IFN inhibition. To determine if r-IFN could directly inhibit the proliferation of a progenitor cell, cells isolated from immature BFU-E-derived colonies, a population enriched for late erythroid progenitors and free of auxiliary cells, were tested; similar inhibition by r-IFN-gamma was observed with these isolated erythroid progenitors as with total bone marrow CFU-E. Although small amounts of r-IFN-gamma also increased inhibition of bone marrow CFU-E-derived colony formation by r-IFN-alpha, no synergy was demonstrable with isolated erythroid progenitor cells. Therefore, even though r-IFN can directly inhibit proliferation of a progenitor cell, auxiliary cells may be required for synergy between r-IFN-gamma and r-IFN-alpha.
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PMID:Studies of interferon as a regulator of hematopoietic cell proliferation. 241 98

Sublethally irradiated CBA/J mice injected with lymph node cells (LNC) of C3H/He mice exhibit aplastic anemia within 3 weeks. Aplastic anemia plasma (AAP) from these mice was found to inhibit granulocyte-macrophage colony (GM-CFU) formation. This inhibitory action was not strain specific and was not generated in donor:host combination involving other strains. AAP also inhibited the formation of colonies derived from leukemic cell lines. Though this activity inhibited GM-CFU, it did not affect erythroid colony formation. Two experiments were performed to examine the mechanism of inhibition. Superoptimal concentrations of recombinant mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) did not reverse AAP-induced inhibition of colony formation. Bone marrow cells preincubated with AAP for 24 h and washed were unchanged in their ability to form GM-CFU colonies. Thus, the inhibitory activity acted neither as a competitive nor a cytotoxic agent. Interferons and certain prostaglandins, known to inhibit colony formation, were not found in active concentrations in AAP. The inhibitory activity of AAP was heat stable, nondialyzable, inextractable with chloroform, precipitable with 50% ammonium sulfate, and had a molecular weight of 100,000 daltons. In contrast, control plasma from mice given only sublethal irradiation and injected with saline had significantly less inhibitory activity, which was not heat stable and was extractable with chloroform. Thus, LNC in certain host mouse strains generate a plasma activity that can inhibit the formation of normal and leukemic GM-CFU colonies.
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PMID:Inhibitor of granulocyte-macrophage colony formation in plasma of mice rendered aplastic by allogeneic lymph node cells. 246 13

Significant progress has been made in recent years in the understanding of the pathogenesis of the two types of hematologic toxicity from chloramphenicol. The common, dose-dependent, reversible bone marrow suppression from chloramphenicol is a consequence of mitochondrial injury. The greater erythroid susceptibility to chloramphenicol appears to be a function of the endogenous mitochondrial amino acid pools. The pathogenesis of aplastic anemia from chloramphenicol treatment remains uncertain. A large body of indirect evidence favors a complex mechanism involving metabolic transformation of the p-NO2 group of chloramphenicol by the predisposed subject, leading to the production of a toxic intermediate causing stem cell damage. A concept is presented wherein metabolites of chloramphenicol generated by intestinal bacteria undergo further metabolic transformation in the bone marrow with in situ production of toxic intermediate. This concept of the marrow being both the metabolic site for the offending agent as well as the target for its toxic metabolites will likely apply to other potential myelotoxins.
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PMID:Chloramphenicol toxicity: 25 years of research. 248 34

All etiologies of acute viral hepatitis are associated with a transient suppression of hemopoiesis and, rarely, with the development of aplastic anemia. Both hepatitis A and hepatitis B viruses directly inhibit the growth and differentiation of human bone marrow progenitor cells in vitro. We now report a similar effect of a non-A, non-B (NANB) hepatitis agent on human bone marrow progenitor cells. Three chimpanzees were inoculated with a putative NANB agent. Coded sera were blindly evaluated for their ability to affect human bone marrow colony formation in vitro. Sera obtained during the acute phase of NANB hepatitis inhibited the in vitro growth of human erythroid (CFU-E, BFU-E) and granulocyte-macrophage (CFU-GM) progenitor cells, compared with sera obtained before inoculation. Sera obtained after remission of both the biochemical and histological hepatitis and sera obtained from a chimpanzee who underwent biochemical but not histological remission did not inhibit the stem cell assays as much as the acute phase sera. These results suggest an approach to identifying the viremic phase of NANB hepatitis. Inhibition of human bone marrow proliferation appears to be a common property of all known hepatitis viruses.
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PMID:Inhibition of human hemopoiesis by non-A, non-B hepatitis virus. 249 12


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