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)

Immunosuppressive therapy can produce hematologic improvement in a large proportion of patients with severe aplastic anemia. Antithymocyte globulin (ATG) is the current treatment of choice for patients who do not have histocompatible sibling donors or who are otherwise inegligible for allogeneic bone marrow transplantation. About 50% of patients respond to an initial course of ATG, and many nonresponders can be salvaged by subsequent treatment with cyclosporine (CsA). To determine whether simultaneous administration of these agents could further improve response rates, we enrolled 55 patients in a therapeutic trial of 4 days of ATG and 6 months of CsA. Among the 51 patients who had not received previous courses of ATG or CsA, 67% had responded by 3 months, and 78% had responded by 1 year (response was defined as an increase in peripheral blood counts sufficient that a patient no longer met the criteria for severe disease). There was a high incidence of relapse (36% actuarial risk at 2 years), but most relapsed patients responded to additional courses of immunosuppression, and relapse was not associated with a significant survival disadvantage. Evolution to myelodysplastic syndromes and acute leukemia was rare (1 of 51 patients), but the later appearance of paroxysmal nocturnal hemoglobinuria was more common (5 of 51 patients). Actuarial survival was 86% at 1 year and 72% at 2 years. These data support the use of a combination immunosuppressive regimen containing both ATG and CsA as first-line therapy for severe aplastic anemia.
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PMID:Intensive immunosuppression with antithymocyte globulin and cyclosporine as treatment for severe acquired aplastic anemia. 775 40

Immune modulating therapy has greatly improved the prognosis in aplastic anaemia, but the response to treatment varies considerably. We describe eight patients who were treated for severe aplastic anaemia. Antithymocyte globulin was given as first line treatment, followed by cyklosporine A if the patient failed to respond. Seven patients entered complete remission, but two of these relapsed later. Both developed paroxysmal nocturnal haemoglobinuria. One patient failed to respond to therapy. She died of bone marrow failure and haemochromatosis 12 months after start of therapy. Immune modulating therapy is discussed in relation to bone marrow transplantation, which is the alternative therapy for younger patients.
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PMID:[Immunomodulating treatment of severe aplastic anemia in adults]. 833 23

Antithymocyte globulin (ATG) is one of the effective drugs used in the treatment of aplastic anaemia (AA). Although it has been speculated that the mechanism of action of ATG is mediated by its immunosuppressive effect on lymphocytes which might have an inhibitory effect on haemopoietic stem and progenitor cells, no definite evidence of the presence of such a mechanism has been demonstrated. In this study we investigated whether such a mechanism is truly operating in ATG therapy for AA. In five patients who responded to ATG, bone marrow cells were obtained after haematological recovery and CD34-positive cells were separated by immunobeads. Autologous CD34-positive cells were mixed with autologous peripheral CD4- or CD8-positive cells obtained before ATG therapy and after haematological recovery, liquid-cultured for 12h, and then cultured in methylcellulose for 14d in the presence of haemopoietic growth factors. In all five cases studied, only the CD8 cells obtained before ATG therapy suppressed the colony forming unit-granulocyte-macrophage (CFU-GM)- and burst forming unit-erythroid (BFU-E)-derived colony formation. This result is definite evidence that one of the mechanisms of action of ATG in AA is an inhibitory effect on CD8-positive cells which have suppressive activity for the growth of haemopoietic progenitor cells.
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PMID:Mechanism of action of antithymocyte globulin in the treatment of aplastic anaemia: in vitro evidence for the presence of immunosuppressive mechanism. 901 91

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day -1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 +/- 37.7 U/l pre-treatment to 1394.4 +/- 488.7 U/l 3 days post-treatment (n = 16; p < 0.029), and then declined to 561.4 +/- 61.3 U/l 10 days post-treatment (n = 16; p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 +/- 11.3 U to 184.6 +/- 74.6 U (n = 16; p < 0.036), and then declined to 121.9 +/- 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 + 5.7 U to 152.0 +/- 67.0 U (n = 16; p < 0.44) and then declined to 46.0 +/- 14 (n = 16; p < 0.049). The mean tau-glutamyltransferase (GTP) levels increased from 93.0 +/- 34 to 188.0 +/- 36 (n = 16; p < 0.02), and were 168.0 +/- 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 +/- 1.9 microM l(-1) to 22.7 +/- 2.8 (n = 16); NS), at day +3 and to 31.9 +/- 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.
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PMID:Impaired liver function tests in patients treated with antithymocyte globulin: implication for liver transplantation. 946 33

Antithymocyte globulin (ATG) is an effective immunosuppressive therapy for aplastic anemia (AA). We administered ATG combined with cyclosporine (CyA), to 9 patients (4 men and 5 women; median age, 55 years). AA was severe in 8 patients and moderate in 1. The ATG and CyA regimen was the initial treatment for 3 patients, but sequential treatment for the other 6, who were refractory to other agents. Peripheral T lymphocytes, including CD4-positive and CD8-positive cells, decreased rapidly after treatment. Although 1 patient died of pulmonary hemorrhage during the 6-month period following treatment with this combined regimen, 3 showed a favorable response, 2 moderate response, and 3 no response at all. Adverse drug reactions, including transient fever and rash, were not severe. These findings suggested that ATG and CyA in combination are a safe and effective immunosuppressive regimen for initial and refractory patients with AA.
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PMID:[Treatment of aplastic anemia with anti-thymocyte globulin and cyclosporine]. 979 96

Antithymocyte globulin (ATG) is a foreign protein used widely to treat aplastic anaemia (AA). Febrile reactions occurring during its administration may be impossible to distinguish clinically from fever due to sepsis, and are therefore routinely treated with intravenous antibiotics after collection of blood cultures. A statistically highly significant difference was found in positive blood cultures between 39 AA patients who developed fever during ATG therapy, and 38 febrile neutropenic patients with acute leukaemia. suggesting that most fevers developing during ATG treatment are not due to infection. It may therefore be reasonable to consider early discontinuation of intravenous antibiotics in patients who are clinically stable and have no proven sepsis.
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PMID:The incidence and significance of fevers during treatment with antithymocyte globulin for aplastic anaemia. 985 44

Immunosuppression is the treatment modality for the majority of patients with aplastic anemia, most of whom are not candidates for allogeneic stem-cell transplantation. Antithymocyte globulin (ATG) or antilymphocyte globulin (ALG) have proven to be essential components of all regimens. Initial response rates can be improved by the addition of cyclosporine A (CsA), and this combination has become the standard of care for appropriate patients. Several new approaches to immunosuppression are being studied, including the optimal timing of administration of these drugs, the use of novel immunosuppressive agents, and the addition of early- and late-acting hematopoietic growth factors.
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PMID:Immunosuppressive treatment of aplastic anemia with antithymocyte globulin and cyclosporine. 1067 11

In aplastic anemia, hematopoiesis fails: Blood cell counts are extremely low, and the bone marrow appears empty. The pathophysiology of aplastic anemia is now believed to be immune-mediated, with active destruction of blood-forming cells by lymphocytes. The aberrant immune response may be triggered by environmental exposures, such as to chemicals and drugs or viral infections and, perhaps, endogenous antigens generated by genetically altered bone marrow cells. In patients with post-hepatitis aplastic anemia, antibodies to the known hepatitis viruses are absent; the unknown infectious agent may be more common in developing countries, where aplastic anemia occurs more frequently than it does in the West. The syndrome paroxysmal nocturnal hemoglobinuria (PNH) is intimately related to aplastic anemia because many patients with bone marrow failure have an increased population of abnormal cells. In PNH, an entire class of proteins is not displayed on the cell surface because of an acquired X-chromosome gene mutation. The PNH cells may have a selective advantage in resisting immune attack. In contrast, the disease myelodysplasia can be confused with aplasia and can also evolve from aplastic anemia. The occurrence of cytogenetic abnormalities in patients years after presentation implies that genomic instability is a feature of this immune-mediated disease. Aplastic anemia can be effectively treated by stem-cell transplantation or immunosuppressive therapy. Transplantation is curative but is best used for younger patients who have histocompatible sibling donors. Antithymocyte globulin and cyclosporine restore hematopoiesis in approximately two thirds of patients. However, recovery of blood cell count is often incomplete, recurrent pancytopenia requires retreatment, and some patients develop late complications (especially myelodysplasia).
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PMID:Acquired aplastic anemia. 1192 89

Antithymocyte globulin (ATG) is the standard therapy for aplastic anemia (AA) patients who are not eligible for allogeneic bone marrow transplantation (BMT). The exact mechanism of action of ATG is still not known. Profound lymphopenia is observed throughout the treatment period with ATG and appears to contribute to its immunomodulatory effect. One of the possible mechanisms, which could account for ATG-mediated lymphopenia, is by induction of apoptosis of peripheral blood mononuclear cells (PBMCs). However, there is no conclusive evidence to support this mechanism. We investigated whether ATG could induce an in vivo apoptosis in PBMCs of 12 AA patients undergoing ATG therapy by terminal deoxynucleotidyltransferase (TdT)-mediated dUTP nick-end labeling (TUNEL) assay using flow cytometry. A significant increase in the percentage of apoptosis was observed in six patients. The median percentage prior to therapy was 3 percent (range: 1-10 percent), which increased to a peak median value of 27 percent (range 17-66 percent) with therapy. ATG also induced an in vitro apoptosis of normal PBMCs as demonstrated by Annexin V and TUNEL staining using flow cytometry. Induction of apoptosis was dose dependent: 52 percent of the PBMCs exhibited Annexin V positivity after incubation with ATG at a dose of 500 microg/ml for 6 h, and 37 percent of the PBMCs exhibited DNA fragmentation after incubation with ATG at a dose of 1000 microg/ml for 24 h as demonstrated by TUNEL assay. Thus, ATG induces in vivo apoptosis in PBMCs of AA patients undergoing therapy as well as an in vitro apoptosis in normal PBMCs, and apoptosis may be an important mechanism for ATG-induced lymphopenia.
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PMID:Induction of apoptosis of peripheral blood mononuclear cells by antithymocyte globulin (ATG) in aplastic anemia: an in vivo and in vitro study. 1202 33

Antithymocyte globulin (ATG) is the treatment of choice for those aplastic anemia patients who are not suitable for bone marrow transplantation (BMT). ATG is also used for the treatment of rejections in organ transplantation and as a conditioning regimen in BMT. Despite the proven efficacy of ATG in these areas, its mechanism of action is not known. Profound T-cell lymphopenia observed in vivo with ATG treatment is supposed to contribute to its therapeutic effect. We have previously shown that apoptosis is one of the mechanisms responsible for ATG-induced lymphopenia. Our next objective was to investigate the effect of ATG on modulation of Fas and TNF pathways, the two main pathways of T-cell apoptosis. Maximum surface expression of Fas on T cells was observed after 24 h at an ATG dose of 100 microg/ml; at this dose 88% of cells expressed Fas as compared to 26% of untreated cells. Surface expression of FasL was found to peak after 24 h at an ATG dose of 1000 microg/ml when 34% of cells were positive for FasL as compared to 1.5% of untreated T cells. Tumor necrosis factor (TNF)-alpha production was found to be maximum after 6 h at 1000 microg/ml dose (20%) as measured by intracellular cytokine staining of T cells. TNF-alpha production was also measured by enzyme-linked immunosorbent assay (ELISA) in the supernatant of lymphocytes treated with ATG for 6 h. A dose-dependent increase in TNF-alpha production was found in these supernatants with a plateau being achieved at an ATG dose of 1000 micro g/ml. We conclude that ATG-induced apoptosis in T cells involves both Fas and TNF pathways and TNF-alpha is produced much earlier than Fas and FasL expression.
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PMID:Involvement of Fas and TNF pathways in the induction of apoptosis of T cells by antithymocyte globulin. 1278 10


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