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Minor population of CD55-CD59- blood cells predicts response to immunosuppressive therapy and prognosis in patients with aplastic anemia

Cellular Transplantation Biology, Division of Cancer Medicine, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi, Kanazawa, Ishikawa 920-8641, Japan.
Blood (Impact Factor: 10.43). 03/2006; 107(4):1308-14.
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ABSTRACT We investigated the clinical significance of a minor population of paroxysmal nocturnal hemoglobinuria (PNH)-type blood cells in patients with acquired aplastic anemia (AA). We quantified CD55-CD59- granulocytes and red blood cells (RBCs) in peripheral blood from 122 patients with recently diagnosed AA and correlated numbers of PNH-type cells and responses to immunosuppressive therapy (IST). Flow cytometry detected 0.005% to 23.1% of GPI-AP- cells in 68% of patients with AA. Sixty-eight of 83 (91%) patients with an increased proportion of PNH-type cells (PNH+) responded to antithymocyte globulin (ATG) + cyclosporin (CsA) therapy, whereas 18 of 39 (48%) without such an increase (PNH-) responded. Failure-free survival rates were significantly higher (64%) among patients with PNH+ than patients with PNH- (12%) at 5 years, although overall survival rates were comparable between the groups. Numbers of PNH-type and normal-type cells increased in parallel among most patients with PNH+ who responded to IST, suggesting that these cells are equally sensitive to immune attack. These results indicate that a minor population of PNH-type cells represents a reliable marker of a positive IST response and a favorable prognosis among patients with AA. Furthermore, immune attack against hematopoietic stem cells that allows PNH clonal expansion might occur only at the onset of AA.

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    • "Detection of PNH-type cells: high-resolution 2-colour flow cytometry We analysed the granulocytes and erythrocytes from the patients using a high-resolution 2-colour flow cytometry as described (Sugimori et al, 2006). Briefly, this assay includes fluorescein isothiocyanate (FITC)-conjugated anti CD55 (anti CD55-FITC; clone IA10, mouse IgG2a; Pharmingen, San Diego, CA, USA) and anti CD59-FITC (clone p282, mouse IgG2a; Pharmingen) antibodies (Abs) combined with phycoerythrin (PE)-labelled anti-lineage marker Ab that increases the specificity of detecting small populations of PNH-type cells. "
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    ABSTRACT: Peripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55(-)CD59(-) [paroxysmal nocturnal haemoglobinuria (PNH)]-type blood cells associated with bone marrow (BM) failure. PNH-type cells were detected in 57% and 20% of patients with AA and RA, respectively. The percentages of PNH-type granulocytes ranged from 0.003% to 94.2% and the distribution was log-normal with a median of 0.178%. Serial analyses of 75 patients with PNH-type cells over 5 years revealed that the percentage of PNH-type cells constantly increased in 13 (17%), persisted in 44 (59%), disappeared in the remaining 18 (24%) although even in the 'Disappearance' group, PNH-type granulocytes persisted for at least 6 months. A scattergram profile of PNH-type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH-type granulocytes sorted from four patients. These findings suggest that the PNH-type cells in patients with BM failure are derived from single PIGA mutant haematopoietic stem cells even when their percentages are <1% and their fate depends on the proliferation and self-maintenance properties of the individual PIGA mutants.
    British Journal of Haematology 07/2009; 147(1):102-12. DOI:10.1111/j.1365-2141.2009.07822.x · 4.96 Impact Factor
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    • "Another marker closely associated with immune pathophysiology in adult AA is paroxysmal nocturnal haemoglobinuria (PNH)-type cells, a type of glycosylphosphatidylinositolanchored protein-deficient cell that are very less in number (Young, 1992; Dunn et al, 1999; Maciejewski et al, 2001; Wang et al, 2001; Saunthararajah et al, 2002). Two retrospective studies have found a correlation between the presence of PNHtype cells and the response to IST in adults with AA (Maciejewski et al, 2001; Sugimori et al, 2006), although a third group failed to find this association (Saunthararajah et al, 2002). "
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    ABSTRACT: Aplastic anaemia (AA) is defined as a pancytopenia caused by bone marrow failure, and its pathogenesis is thought to involve autoimmune processes. Several predictive markers of the response to immunosuppressive therapy (IST) have been proposed, which appear to reflect the immune pathophysiology. We prospectively investigated the presence of human leucocyte antigen (HLA)-DR15, a minor population of paroxysmal nocturnal haemoglobinuria (PNH)-type cells, and antibodies to the recently identified autoantigen postmeiotic segregation increased 1 (PMS1) in 103 children with AA enrolled in a multicentre study. In contrast to adults, children with AA did not show an increased frequency of HLA-DR15. In addition, a sensitive flow cytometric assay revealed that children with AA have a much lower prevalence of PNH-type cells (21.4%) than reported for adults with this disease. An immunoblotting assay detected anti-PMS1 antibody in 15 of 103 (14.6%) of the children. Finally, the response rate to IST was not significantly different between patients with and without DR15 (45.5% vs. 54.0%), PNH-type cells (68.2% vs. 53.1%) or anti-PMS1 antibody (40.0% vs. 59.1%). The current study did not confirm a correlation between these markers and the response to IST, suggesting that there is a difference in the pathophysiologies of adult and paediatric AA.
    British Journal of Haematology 07/2008; 142(3):427-35. DOI:10.1111/j.1365-2141.2008.07182.x · 4.96 Impact Factor
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