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)

Antithymocyte and antilymphocyte globulins (ALG) are currently used as immunosuppressive agents in organ transplantation and for the treatment of acute graft-versus-host disease and aplastic anemia. Since any type of immunosuppressive treatment is known to carry the risk of developing B-cell lymphoproliferative disorders, we investigated the in vitro effect of ALG on human B-cell activation and proliferation. The data demonstrate that whatever the source of lymphocytes used for ALG preparation (thymocytes, thoracic duct lymphocytes, B- or T-cell lines), (1) ALG react with both B- and T-cell lines, and (2) ALG contain antibodies specific for B cells (eg, CD21) or common to T and B cells (eg anti-beta 2-microglobulin, anti-HLA-DR, CD18, CD11a) in addition to T-cell-specific antibodies. Unlike all other T-cell mitogens tested (Concanavalin A [Con A], Pokeweek mitogen [PWM], CD3 and CD2 antibodies), ALG do not trigger B-cell differentiation into immunoglobulin-secreting cells at concentrations which induce maximum T-cell proliferation. This effect could be attributed to a direct interaction of ALG with B lymphocytes as shown by the capacity of ALG to block the response of purified B cells to a variety of activators. Furthermore, all the ALG tested were shown to inhibit the proliferation of six of the seven Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines and six of the seven Burkitt's lymphoma cell lines studied. This selective B-cell antiproliferative property of ALG was not reproduced with CD11a, CD18, CD21, CD24, or anti-HLA-DR monoclonal antibodies (MoAbs). These results suggest that, although suppressing T-cell responses, ALG treatment may directly control B cell proliferation to some extent, in keeping with the relatively low risk of posttransplant lymphoproliferative disorders reported with ALG.
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PMID:Antiproliferative effect of antilymphocyte globulins on B cells and B-cell lines. 156 43

Peripheral blood lymphocytes from 25 allogeneic bone marrow transplant recipients were studied serially using flow cytometry and two colour analysis. Fourteen patients were transplanted for haematologic malignancies, eight for aplastic anaemia, two for congenital immunodeficiencies and one for Morquio's disease. All patients were alive more than 100 days post-grafting; nine patients had chronic graft-versus-host disease (GVHD). Dual labelling with monoclonal antibodies, CD4/2H4, CD4/4B4, CD8/CD11, CD8/HLA-DR and CD8/Leu 7 was used to analyse the surface phenotypes of lymphocytes. The population of CD4+2H4+ cells was decreased, and CD8+CD11+, CD8+CD11- and CD8+Leu7+ cells were markedly increased in patients with chronic GVHD. The increase of CD8+CD11+, CD8+CD11- and CD8+Leu7+ cells closely correlated with clinical signs of chronic GVHD in each patient. These results suggest that CD8+ cells may play an important role in effector and/or suppressor mechanisms of chronic GVHD and could be used as an indicator of need for and response to treatment.
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PMID:Increased numbers of CD8+CD11+, CD8+CD11- and CD8+Leu7+ cells in patients with chronic graft-versus-host disease after allogeneic bone marrow transplantation. 169 37

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

The current working hypothesis on the pathogenesis of autoimmune disease focuses on the interactions between susceptibility genes and environmental stimuli. In Graves' disease it is postulated that aberrant expression of HLA class II antigens on thyroid epithelial cells permits the presentation of specific thyroid antigen to activated lymphocytes. Evidence suggests that thyrocyte HLA-DR expression is secondary to the production of cytokines by presensitized T-lymphocytes. A 20-yr-old woman and her 18-yr-old brother presented with classical findings of Graves' disease with ophthalmopathy within a year of each other. Diagnosis was confirmed by demonstration of elevated serum levels of T4 and T3, strongly positive titers of TSH binding inhibitory immunoglobulins, and histological examination after subtotal thyroidectomy. Eight years previously, acute life-threatening aplastic anemia in the brother led to therapeutic transplantation of bone marrow from his sister. After the procedure, 100% of his peripheral leucocytes were genotype 46,XX. HLA typing performed before transplantation and 2 months after thyroidectomy in the female indicated complete identity with her brother's leukocytes for class I and class II antigens. Thyroid autoantibodies at this time were weakly positive. Although the concordance of thyroid disease in these patients could be due to chance, the patients were of different sexes, the family history was negative, and neither the probands nor the first degree relatives bore the HLA-DR3/B8 antigens. We propose that the male passively acquired a clone of programmed or activated lymphocytes from his sister and that his hyperthyroidism was not primarily dependent on exposure to specific thyroid-derived antigen.
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PMID:Concordant Graves' disease after bone marrow transplantation: implications for pathogenesis. 200 10

Human recombinant granulocyte-macrophage colony-stimulating factor (rhGM-CSF) was administered to 14 patients with refractory aplastic anemia (AA). The effect of rhGM-CSF therapy on the lymphocyte phenotype; on the proliferative responses to the mitogen phytohemagglutinin, Candida albicans, and tetanus toxoid antigens; and on the natural killer (NK) activity of the circulating lymphocytes was studied. Samples were collected before (baseline) and twice during the rhGM-CSF administration. The absolute number of circulating lymphocytes remained relatively constant during the first period, but experienced a significant increase (P less than .001) during the second period. The increase was most prominent in the B cells (P less than .001), but the T cells (P less than .016) also increased. Detailed investigation of lymphocyte subsets showed an increase of the markers CD38 (Leu17), HLA-DR, and the transferrin receptor throughout the treatment course giving evidence of lymphoid cell activation. The NK cell activity was suppressed (P less than .008) throughout the treatment. However, proliferative responses to phytohemagglutinin, Candida antigen, and tetanus toxoid were unaffected. Although the mechanism is not yet defined, GM-CSF does induce activation and increase in absolute lymphoid cell number, especially B cells, together with a decrease in NK cytotoxicity. The implication of these immune cell changes in relation to host resistance to microorganisms remains to be established.
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PMID:Effect of recombinant human granulocyte-macrophage colony-stimulating factor administration on the lymphocyte subsets of patients with refractory aplastic anemia. 220 31

A total of 16 children with aplastic anemia were investigated, among them 6 girls and 10 boys, the mean age 10.5 years. Splenectomy was included into the complex of treatment along with glucocorticoid and transfusion-replacement therapy of all the children. The membrane markers of splenic lymphocytes were assayed in the indirect immunofluorescence test with monoclonal antibodies of ICO and OKT series. The mean parameters did not significantly differ from those of subpopulations of splenic lymphocytes in the control group described in the literature. An individual analysis made in 8 patients (50%) has revealed active lymphocyte populations in the spleen: in the group of patients with a favourable prognosis to the disease an increase in the percent of B-cells was recorded in 2, OKT8(+)-lymphocytes in 1 patient; a rise in the percent of cells with receptors to interleukin-2 in 3 patients (from 25 to 32%); in the group of patients with severe aplasia an increase in the percent of activated HLA-DR(+)-lymphocytes was recorded in 2, and OKT8(+)-lymphocytes in 1 patient. All the patients responded well to the treatment. It has been suggested that in all cases the splenectomy effect is associated with the removal of immunoactive lymphocytes and can serve as an equivalent of the immunosuppressive therapy. The effect of splenectomy in the rest cases has been obscure.
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PMID:[Membrane markers and interleukin-2 receptor of splenic lymphocytes in children with aplastic anemia: detection of active subpopulations]. 225 57

The expression of lymphocyte surface markers as well as the production of interleukin-2 (IL-2) and interferon-gamma (IFN) by mitogen-stimulated peripheral blood mononuclear cells (MNC) have been studied in five children with constitutional aplastic anemia. A significantly reduced T4/T8 ratio was found and two of five patients also had a reduced percentage of B cells. One patient had a high percentage of HLA-DR positive T8+ cells, very suggestive of a high degree of circulating activated T suppressor/cytotoxic cells. IL-2 production was reduced in two patients, whereas IFN production was only reduced in one of these. The abnormalities found correlate with the duration of the bone marrow failure. The patients with the longest duration of bone marrow failure also exhibited the lowest T4/T8 ratio. No spontaneous IFN production was detected in any of the patients. There was no clinical benefit or reversal of the immune abnormalities during and following treatment with cimetidine and cyclosporine A in two patients.
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PMID:Lymphocyte subpopulations and lymphokine production in children with constitutional aplastic anemia. 248 52

The short-term effect of a domestically produced equine antithymocyte globulin (ATG) was analyzed in 6 patients with acquired severe aplastic anemia (AA). All patients received 5 doses of ATG every other day in a 60-min intravenous infusion. Five peripheral blood immunoregulatory mononuclear cell (MNC) subsets, defined by monoclonal antibodies, were enumerated before and 24 h after each application of ATG. Following the first dose of ATG there was a significant and transient reduction in the absolute number of helper T lymphocytes. There was no statistically significant difference pre-ATG to post-ATG in the absolute number of MNC expressing activation antigen Tac (interleukin-2 receptor). However, Tac+ cells, which were significantly increased before ATG therapy, decreased to nearly normal levels after the fourth dose of ATG. A significant and sustained increment in the absolute number of monocytes (CD14+ cells) occurred following the third dose of ATG. The absolute numbers of MNC, suppressor T lymphocytes and cells bearing HLA-DR antigen remain without significant change along ATG treatment. These results suggest that: (a) Tac+ cells are probably involved in the pathogenesis of AA; (b) the target of ATG may be a Tac+ cell, and (c) ATG may stimulate monopoiesis.
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PMID:Changes in peripheral blood mononuclear cell subpopulations during antithymocyte globulin therapy for severe aplastic anemia. 250 90

In patients with severe aplastic anemia (SAA), lymphocyte subpopulations were examined for the presence of HLA-DR and 2H4 (suppressor/inducer subset) antigen-expressing cells by flow cytometric analysis. Investigations were performed on peripheral blood lymphocytes before and after therapy with antithymocyte globulin (ATG) and methylprednisolone (MP), as well as on bone-marrow lymphocytes before therapy. Before treatment, only the absolute numbers of CD4+ T cells and the CD4+HLA-DR+/CD8+HLA-DR+ activated T cell ratio were significantly decreased (p less than 0.01 and p less than 0.001, respectively). Following successful ATG/MP treatment, a decrease in the CD4+/CD8+ T cell ratio was found. Regarding the suppressor/inducer subset, only absolute numbers of CD4+/2H4+ cells were somewhat higher in treated patients; the percentages were the same in all groups of patients. Studies performed on bone-marrow lymphocytes showed significantly decreased percentages of CD4+ and CD8+ T lymphocytes, which also express HLA-DR antigen. No significant changes in the distribution of activated T cells following ATG/MP therapy were found, suggesting that these cells play no major role in the pathogenesis of the disease.
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PMID:Identification of activated T cells and the suppressor/inducer subset in patients suffering from severe aplastic anemia. 252 3

We studied the mechanism of hematopoietic suppression in aplastic anemia by means of two-color flow microfluorometric analysis of lymphocyte subpopulations and correlated the results with the occurrence in vitro of hematopoietic suppression and interferon production. In 12 patients with aplastic anemia a striking increase was observed in a population of "activated" suppressor T lymphocytes, which were defined by binding of both anti-Leu-2 and anti-HLA-DR monoclonal antibodies (patients with aplastic anemia, 6.8 +/- 3.2 per cent [mean +/- S.D.]; normal subjects, 1.7 +/- 1.3; patients given multiple transfusions, 2.5 +/- 1.7). Tac antigen expression, another surface marker of lymphocyte activation, was increased on suppressor lymphocytes in all five patients examined (patients with aplastic anemia, 31 +/- 17 per cent; normal subjects, 0.7 +/- 0.24; patients given multiple transfusions, 2.3 +/- 1.2). When Tac+ and Tac- cells were separated in a cell sorter, only Tac+ cells produced interferon. When lymphocytes of patients with aplastic anemia were cocultured with normal bone marrow, only the Tac+ cell fraction showed hematopoietic suppressor activity. In one patient, in vitro elimination of suppressor lymphocytes by use of OKT8 antibody abolished spontaneous interferon production by bone-marrow cells. These results suggest that activated suppressor lymphocytes producing interferon have a role in the pathogenesis of bone-marrow failure, and indicate the usefulness of defined lymphokine and phenotypic markers in the study of aplastic anemia.
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PMID:Circulating activated suppressor T lymphocytes in aplastic anemia. 298 6


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