The mechanism of T cell lymphopenia in myelodysplastic syndromes (MDS) is unknown. We investigated apoptosis in freshly isolated and cultured lymphocytes; the latter were used to detect cells not yet apoptotic but destined for apoptosis. Apoptosis increased in both fresh and cultured T cells in MDS compared with those from healthy controls. Furthermore, in lymphopenic MDS patients the lymphocyte count correlated negatively with the degree of T cell apoptosis. MDS T cells showed increased Fas expression. However, in MDS but not in controls, the degree of T cell apoptosis was independent of the Fas expression level, and exogenous anti-Fas antibodies did not modulate T cell apoptosis. Mechanisms other than the Fas-Fas ligand pathway may induce T cell apoptosis in MDS.
[Show abstract][Hide abstract] ABSTRACT: To better estimate prognosis for patients with myelodysplastic syndromes (MDS) associated with clonal interstitial deletions of the long arm of chromosome 5 (del(5q)), we reviewed the medical records of 130 adults with del(5q) MDS seen at our institution over a 15-year period. Overall median survival of this cohort was 9.5 months, shorter than reported in earlier series. The least favorable outcomes are associated with complex cytogenetics, lack of any normal metaphases, normocytic rather than macrocytic erythrocyte indices, and low baseline lymphocyte counts. Lymphopenia but not neutropenia at the time of diagnosis appears to be a new adverse prognostic indicator. Cytogenetic breakpoints defined by G-banded karyotyping correlate poorly with particular disease features. Surprisingly, survival of patients with treatment-related MDS was equivalent to that of de novo MDS with del(5q) in this series. Morphologic features associated with del(5q) are diverse. Most patients with del(5q) MDS do not meet criteria for WHO-defined 5q-syndrome, and the presence of del(5q) does not appear to modify the clinical phenotype otherwise risk-stratified by the International Prognostic Scoring System (IPSS). Additional important prognostic factors not taken into account by the IPSS include the baseline erythrocyte indices, lymphocyte count, and clonal burden.
American Journal of Hematology 09/2008; 83(9):708-13. DOI:10.1002/ajh.21245 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Clinical data suggest that CD7+ myeloblasts are linked with poor prognosis in myeloid malignancies including myelodysplastic syndromes (MDS). To explore the biology behind this, we compared cell characteristics between CD34+CD7+ and CD34+CD7- myeloblasts from an MDS cell line and fresh samples from MDS patients. Compared with CD34+CD7- myeloblasts, CD34+CD7+ myeloblasts showed greater proliferative capacity, more active cell cycling, and less apoptosis. In analyses of a cell line, CD34+CD7+ myeloblasts produced CD34+CD7- myeloblasts and showed lower expressions of interleukin-8 and chemokine (C-C motif) ligand 2 genes, suggesting immaturity of these cells. These findings might underlie the clinical aggressiveness in CD7+ MDS.
Leukemia research 09/2008; 33(2):326-31. DOI:10.1016/j.leukres.2008.07.006 · 2.35 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The capacity of mononuclear blood cells to form autoreactive cytotoxic T lymphocytes was investigated in order to elucidate the mechanism of successful immunosuppressive therapy in some myelodysplastic syndrome (MDS) patients (autoreactivity studies). The failure in autoreactivity studies raised the question of alloreactive cytotoxic T lymphocyte formation in MDS (alloreactivity studies).
Sixteen MDS patients and relevant controls were examined. Autoreactive lymphocytes directed against autologous bone marrow mononuclear cells and alloreactive lymphocytes directed against unrelated third-party cells were tested using cytotoxicity assay. In addition, we used one-way mixed lymphocyte reaction, human androgen receptor test for clonality detection, and enzyme-linked immunosorbent assay kits for tumor necrosis factor and interferon-gamma testing.
We did not confirm the presence of autoreactive T cells in eight of nine MDS patients tested. The response to allogeneic cells was impaired in 11 of 16 MDS patients, more often in refractory anemia (RA; 80%) than in RA with ring sideroblasts (40%). Interestingly, the response to allogeneic cells in mixed lymphocyte reaction was normal in all MDS patients. T lymphocytes were polyclonal in all but one patient. Tumor necrosis factor and interferon-gamma level in supernatants of mononuclear cells was significantly reduced in RA.
The presumed autoaggressive T cells were not confirmed in MDS in our experimental arrangement. Alloreactivity studies demonstrated the impairment of effector cytotoxic phase of cell-mediated immunological reaction in MDS, namely in RA. The significance of our finding of defective cytotoxicity for pathogenesis, clinical course, and even for therapy is discussed together with other immunological defects reported so far.
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