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)

To determine the mechanism by which haematopoiesis is suppressed in aplastic anaemia, the effect of the sera from 6 patients on the granulopoietic precursors (colony-forming units in culture; CFU-C) was studied in vitro. Addition of the sera from 2 patients significantly suppressed CFU-C. The suppressive effect of the sera on CFU-C was inhibited by the addition of 1.5 NU/ml of anti-gamma-IFN antibody. In another patient, anti-gamma-IFN antibody increased autologous CFU-C although the serum of the patient did not suppress CFU-C. Serum gamma-IFN levels of all patients were under 2 IU/ml. The above findings suggest that humoral factors inhibit haematopoiesis in some patients with aplastic anaemia, and that gamma-IFN plays a role as an inhibitor even at a low concentration.
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PMID:Haematopoietic suppressing activity of gamma-interferon in serum and bone marrow of aplastic anaemia patients. 210 20

In an ongoing phase-II trial we aimed to predict clinical responsiveness of Philadelphia chromosome positive (Ph1+) chronic myelogenous leukaemia (CML) to recombinant IFN-alpha-2C (rIFN-alpha-2C) by pretesting in vitro. From five normal controls and 14 CML patients in chronic phase, bone marrow samples were taken before treatment and tested for antiproliferative activity by rIFN-alpha-2C, using a microagar culture system for BFU-E, CFU-GM, and CFU-Meg. Light-density nucleated bone marrow cells were stimulated for BFU-E and CFU-Meg colony formation with Alpha medium containing 20% serum obtained from a patient with severe aplastic anaemia. CFU-GM growth was induced with conditioned medium from the cell line GCT. In normal controls BFU-E, CFU-GM and CFU-Meg colony formation was inhibited by rIFN-alpha-2C in a dose-dependent manner. BFU-E proved to be the most sensitive cell lineage (IC50: 65; range: 53-116 U/ml) whereas CFU-GM was about 20 times less sensitive (IC50: 643; range: 480-897 U/ml). The sensitivity of CFU-Meg ranged between these two colony types with 50% growth inhibition at an IFN concentration of 160 (range: 68-246 U/ml). A heterogeneous response to rIFN-alpha-2C in vitro was seen in CML patients. Three of the 14 patients were 'resistant' to rIFN-alpha-2C in vitro with IC50 values for BFU-E, CFU-GM and/or CFU-Meg colony formation greater than 10(4) U/ml. Patients were subsequently treated with a daily dose of rIFN-alpha-2C of 5 x 10(6) U. Four patients achieved a complete and six achieved a partial haematological response. Of the four non-responders three rapidly progressed into blastic crisis. Thus it was seen that treatment failure to interferon was accompanied by IFN-resistance in vitro of BFU-E, CFU-GM and/or CFU-Meg colony formation by bone marrow precursors (p less than 0.01). These results suggest a predictive value of IFN-sensitivity testing in vitro in Ph1 + CML.
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PMID:Recombinant interferon-alpha-2C in chronic myelogenous leukaemia: relationship of sensitivity of committed haematopoietic precursor cells in vitro (BFU-E, CFU-GM, CFU-Meg) and clinical response. 238 74

The mechanism which produces marrow failure in idiopathic aplastic anemia is still unknown. Recent investigations have suggested the crucial role of NK cells in the regulation of normal hematopoiesis. In this study, the cytotoxic activity of mononuclear cells from human bone marrow and peripheral blood was examined against three NK-sensitive target cell lines in 15 patients with aplastic anemia as well as 21 normal subjects. Marrow mononuclear cells from aplastic anemia demonstrated a high cytotoxicity comparable to peripheral blood NK cells to these target cells. Neither large granular lymphocytes nor the cells expressing known NK cell surface phenotypes increased in aplastic marrow cell elements. The aplastic marrow cells showed strong killing activity rather than binding at single cell assay. They consisted of non-adherent and adherent cell population in plastic adherence and were unresponsive to IFN treatment. The existence of cytotoxic cells with high NK-like activity may be responsible for the mechanism of marrow failure in aplastic anemia.
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PMID:High cytotoxic cell activity in the marrow from patients with aplastic anemia. 258 85

Two patients with aplastic anaemia were treated with immunosuppressive agents and peripheral blood T cells were cryopreserved serially. Inhibitory activity of T cells to autologous CFU-E, gamma-IFN production by T cells and T cell subpopulations were assayed after remission. Inhibitory activity to autologous CFU-E was not correlated with the numbers or ratios of T cell subpopulations. gamma-IFN production by T cells were within the normal range when inhibitory activity was found. In addition, gamma-IFN production increased after haematopoietic recovery. These findings suggest that gamma-IFN is not a soluble mediator of T cell-mediated haematopoietic inhibition in aplastic anaemia.
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PMID:No evidence for gamma-interferon mediated haematopoietic inhibition by T cells in aplastic anaemia: an observation in the course of immunosuppressive therapy. 311 31

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

Peripheral blood mononuclear cells (PBMC) from patients with aplastic anemia (AA) and healthy donors were compared with regard to their ability to produce soluble factors with inhibitory activity on in vitro granulopoiesis (GM-CFC). Although PBMC from AA patients produced enhanced levels of IFN-gamma as compared to controls, this lymphokine was found not to be the main inhibitor of in vitro granulopoiesis. Other, non-IFN related factors were potent inhibitors of both the mature and the immature precursors for GM-CFC, could act across the species barrier and were of low molecular weight. Also PBMC from healthy donors produced a non-IFN mediated GM-CFC inhibitory factor, but to a lesser degree and acting only on one type of myeloid precursors. The possible implications of these findings in relation to the etiology of AA will be discussed.
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PMID:IFN-gamma is not the only mediator of suppressed myelopoiesis produced by mononuclear cells from aplastic anemia patients. 314 16

Growth and differentiation of hematopoietic progenitor cells is regulated by a complex network of stimulatory and inhibitory cytokines. Bone marrow failures can be due to a decrease of stimulators or an increase of inhibitors. T cells produce both, hematopoiesis stimulating and inhibiting cytokines. Therefore, a role of T cells in regulating hematopoiesis can only be assumed if the gene expression of these antagonistic acting cytokines can be differentially induced in T cells. To establish a model of selective cytokine induction, we investigated the induction of IFN gamma as inhibitor and GM-CSF as stimulator of hematopoiesis in T cells. Our results showed that IFN gamma mRNA accumulates in T cells which have been pre-activated via the signal transduction unit CD3, but not in unstimulated T cells. This accumulation depends on the expression of the high affinity IL2 receptor which is including the IL2 receptor alpha-chain (IL2R alpha, CD25). In a study on children with constitutional (CAA) versus acquired aplastic (EAA) anemia, we investigated the relevance of this model for the pathogenesis of aplastic anemia in childhood. We compared the following parameters: 1. Incidence of hematopoietic progenitor cells and cloning efficiency, 2. activation status and IL2R alpha expression of bone marrow T cells, 3. T cell cytokine expression profile. Our results show: 1. The relative incidence of bone marrow progenitor cells is decreased in children with CAA and normal in children with EAA. 2. Clonogenic growth of hematopoietic progenitor cells is suppressed in children with EAA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Experimental principles of therapy-oriented pathogenetic classification of aplastic anemia in childhood]. 796 17

Improved survival of patients with aplastic anaemia (AA) has been reported over the last 20 years with immunosuppressive (IS) therapy using antilymphocyte globulin (ALG), and more recently cyclosporin (CSA). The antibody specificities of ALG have now been more clearly defined and are not only T cell directed but also include activities against B cells, NK cells and monocytes. Consequently, the effectiveness of ALG in AA may involve several different mechanisms, and may also help to explain the delayed response that occurs in AA. CSA increases the response rate to ALG in the first 3-6 months, but does not result in improved survival compared with ALG alone. Better supportive care has undoubtedly contributed to the improved survival of patients with time. Almost half the patients who do not respond to a first course of ALG can achieve a later response with a second course of ALG. Relapse occurs in 30% of patients, but up to 50% will respond again with a second course of ALG. Evaluation of the expression of (1) phosphatidylinositol-glycan (PIG)-anchored proteins on haemopoietic cells and (2) gamma-IFN in bone marrow mononuclear cells, may help to predict which patients are more likely to respond to IS therapy. Long term follow up of patients is required to assess the predictive value of X-inactivation DNA studies and PIG-protein expression for later clonal evolution.
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PMID:Treatment of aplastic anaemia with antilymphocyte globulin and cyclosporin. 858 57

Antibodies to IFN-alpha have been recognized as a novel type of autoantibody developing after allogeneic BMT. Ninety-six patients undergoing BMT for various hematologic disorders were followed for the presence of spontaneous IFN-alpha antibodies until 12 years after transplantation. Seven of them (7.3%) developed IFN-alpha antibodies occurred late after BMT (> or = 15 months), rose to very high titers in some patients, and persisted for years despite combined immunosuppressive treatment. They were oligo- or polyclonal in nature, predominantly IgG with a broad IgG subclass distribution, and neutralized the antiviral and antiproliferative activity of various natural and recombinant IFN-alpha types including the patients' endogenous IFN-alpha in vitro. All antibody-positive recipients suffered from chronic GVHD (n = 5) or chronic viral hepatitis (n = 2), but the only significant association was with prior severe aplastic anemia (3/9, 33%; P = 0.022). There was no discernible HLA association of IFN antibody development. Although the clinical relevance of the IFN-alpha antibodies is uncertain they may interfere with cellular defence mechanisms and immune regulation after BMT.
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PMID:Antibodies to interferon-alpha: a novel type of autoantibody occurring after allogeneic bone marrow transplantation. 872 65

Cytokines, by definition, exert an effect on haematopoiesis. Diseases characterized by haematopoietic insufficiency, such as aplastic anaemia, should therefore be investigated for abnormal expression of these regulatory proteins. In studies on hairy cell leukaemia, a severe deficiency was found in the production of interleukin-3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF), granulocyte CSF, IL-6 and tumour necrosis factor alpha (TNF alpha). Further studies on IL-6 at the mRNA and protein levels revealed that peripheral blood mononuclear cells and even hairy cells could be stimulated by interferon alpha (IFN alpha) to produce IL-6. It is interesting to speculate on the beneficial effects of IFN alpha therapy on the expansion of normal haematopoiesis and suppression or even elimination of malignant cells. Studies on a patient with angio-immunoblastic lymphadenopathy, another disease showing haematopoietic insufficiency, who developed severe aplastic anaemia, showed massive increases in IFN gamma and TNF alpha levels in serum; IL-6 and GM-CSF levels were below the limit of detection. These results correlated with an abnormal distribution of CD4+ and CD8+ T lymphocytes in the patient's blood and were compatible with the suppressive effects of IFN gamma and TNF alpha on haematopoiesis.
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PMID:The role of cytokines in haematopoiesis. 898 45


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