The treatment of severe acquired aplastic anemia

Young, NS; Barrett, A. John

doi:10.1182/blood.v85.12.3367.bloodjournal85123367

Cited by 167 publications

(58 citation statements)

References 69 publications

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“…Androgens, however, may be used as an adjunctive therapy in patients that are refractory to immunosuppression. 22 High doses of corticosteroids may induce hematologic response in human patients, but antilymphocyte globulin and cyclosporine are preferred because of the adverse effects of corticosteroids. 22 Inclusion criteria for a diagnosis of aplastic pancytopenia in human beings are specific and well defined.…”

Section: Discussionmentioning

confidence: 99%

“…22 High doses of corticosteroids may induce hematologic response in human patients, but antilymphocyte globulin and cyclosporine are preferred because of the adverse effects of corticosteroids. 22 Inclusion criteria for a diagnosis of aplastic pancytopenia in human beings are specific and well defined. They include: hemoglobin concentration ,10 g/dL, reticulocytopenia, platelet count ,50 3 10 3 /lL, neutrophil count ,1.5 3 10 3 /lL, and hypocellular bone marrow aspirate and core biopsy specimens.…”

Section: Discussionmentioning

confidence: 99%

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A retrospective study of aplastic pancytopenia in the dog: 9 cases (1996–2003)

Brazzell

Weiss

2006

Veterinary Clinical Pathol

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

A retrospective study of aplastic pancytopenia in the dog: 9 cases (1996–2003)

Brazzell

Weiss

2006

Veterinary Clinical Pathol

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“…The pathogenesis of AA is complex and there is much debate as to whether AA is an immune-mediated disease (Young & Barrett, 1995). Long-term bone marrow cultures have demonstrated a defect in the ability of the haemopoietic stem cells to proliferate and differentiate, and cross-over studies have shown that AA stroma usually functions normally in its ability to support normal stem cells.…”

Section: Discussionmentioning

confidence: 99%

Effects of antithymocyte globulin on bone marrow CD34+ cells in aplastic anaemia and myelodysplasia

et al. 2000

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Summary. The mechanism of action of antithymocyte globulin (ATG) in the treatment of aplastic anaemia (AA) and myelodysplastic syndromes (MDS) is poorly understood and may involve many different mechanisms. The aim of this in vitro study was to investigate further the effect of ATG on haemopoietic progenitor cells. A total of 16 patients (10 AA and 6 MDS) and 12 normal control subjects were studied. Puri®ed bone marrow (BM) CD34 cells were cultured in committed progenitor assay in the presence of ATG and autologous serum, then scored on day 14 for granulocyte± monocyte colony-forming units (CFU-GM) and erythroid colonies. ATG was found to be inhibitory to haemopoietic progenitor cells at high concentrations (1000 mg/ml and 100 mg/ml). This was con®rmed by CD34-FITC and 7AAD staining of puri®ed normal CD34 cells after overnight incubation with ATG. In contrast, at lower doses (0´1± 10 mg/ml), ATG produced an increase in colony growth in most normal, MDS and AA BM CD34 cells. The greatest effect was in patients with non-severe AA, in whom the greatest increase in CFU-GM was seen at 0´5 mg/ml (P < 0´02) and 0´1 mg/ml (P 0´02) and erythroid colonies at 0´1 mg/ml (P < 0´05). Serum ATG levels peaked during infusion to levels that were found to be toxic to haemopoietic progenitor cells in vitro and fell thereafter to levels that were associated with the highest colony numbers (0´1 and 0´5 mg/ml) in vitro. These results suggest that an increase in haemopoietic progenitor cells by ATG may be one of several important mechanisms for haematological recovery in AA and MDS.

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“…Evidence for the T-cellmediated pathogenesis of AA is found in the response of 70% of the patients treated with immunosuppressives, i.e. anti-lymphocyte globulin (ALG)/anti-thymocyte globulin (ATG) and cyclosporin A (Young & Barrett, 1995;Frickhofen et al, 1991). An increased percentage of CD8 HLA-DR T cells in PB and BM has been found (Zoumbos et al, 1985;Maciejewski et al, 1994) as well as a significant association of AA with the HLA-DR2 allele (Nimer et al, 1994;Nakao et al, 1994).…”

mentioning

confidence: 99%

Analysis of T‐cell clonality in bone marrow of patients with acquired aplastic anaemia

Melenhorst¹,

Fibbe²,

Struyk

et al. 1997

Br J Haematol

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Summary. Acquired aplastic anaemia (AA) represents a state of bone marrow (BM) failure which is characterized by BM hypocellularity and pancytopenia. It has been hypothesized that in some AA patients, bone marrow failure is secondary to the targeted destruction of haemopoietic stem cells by autoreactive T cells. The response of T cells to antigenic stimulation has been shown, in a number of animal models and in autoimmune diseases, to result in the (oligo)clonal expansion of positively reacting T cells. For this reason, we studied the utilization of 24 T-cell receptor-variable gene segments (TCRBV) and the clonality in BM aspirates and peripheral blood (PB) of seven AA patients. BM from transplant donors served as controls. Determination of TCRBV gene segment usage revealed no significant differences between patients and controls.Clonality within each family was analysed by singlestrand conformation polymorphism (SSCP) analysis. Clonal and clonally predominant bands were seen in BM of three AA patients in five to eight TCRBV families. Clonal rearrangements were encountered less often in BM of control subjects. In conclusion, our results suggest an antigen-driven T-cell response in the BM of predominantly AA patients resulting in oligoclonal T-cell outgrowth.Keywords: aplastic anaemia, clonality, T-cell receptor-, SSCP, V usage.Aplastic anaemia (AA) is an acquired disorder affecting haemopoietic stem cells and is characterized by a reduced bone marrow (BM) cellularity and pancytopenia. Previously, we have studied the clonality of haemopoiesis in peripheral blood (PB) cells of female patients, who entered remission after anti-thymocyte globulin (ATG) therapy. Employing a PCR-based X-chromosome inactivation analysis, it was shown that about half of the patients exhibited clonal haemopoiesis (Van Kamp et al, 1991;Melenhorst et al, 1996). Analysis of the rearrangement patterns at the T-cell receptor-and immunoglobulin heavy chain loci by PCR revealed a polyclonal character of gene rearrangements, irrespective of the X-chromosome inactivation status of the lymphocyte populations.Clonal haemopoiesis in AA may result from a reduced stem cell pool to a clonal composition. It has been hypothesized that in a subgroup of AA patients this reduction is caused by autoreactive T lymphocytes (Young, 1992), recognizing an autoantigen expressed on haemopoietic progenitor cells. Evidence for the T-cellmediated pathogenesis of AA is found in the response of 70% of the patients treated with immunosuppressives, i.e. anti-lymphocyte globulin (ALG)/anti-thymocyte globulin (ATG) and cyclosporin A (Young & Barrett, 1995;Frickhofen et al, 1991). An increased percentage of CD8 HLA-DR T cells in PB and BM has been found (Zoumbos et al, 1985;Maciejewski et al, 1994) as well as a significant association of AA with the HLA-DR2 allele (Nimer et al, 1994;Nakao et al, 1994). The association of an HLA-allele with autoimmune disease predisposition is one of the most clearly established factors, and is related to the MHC-restricted T-cell response (T...

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The treatment of severe acquired aplastic anemia

Cited by 167 publications

References 69 publications

A retrospective study of aplastic pancytopenia in the dog: 9 cases (1996–2003)

A retrospective study of aplastic pancytopenia in the dog: 9 cases (1996–2003)

Effects of antithymocyte globulin on bone marrow CD34+ cells in aplastic anaemia and myelodysplasia

Analysis of T‐cell clonality in bone marrow of patients with acquired aplastic anaemia

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