Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

Sloand, Elaine M.; Mainwaring, Lori; Führer, Monika; Ramkissoon, Shakti; Risitano, Antonio M.; Keyvanafar, Keyvan; Lu, Jun; Basu, Atanu; Barrett, A. John; Young, Neal S.

doi:10.1182/blood-2004-05-2017

Cited by 163 publications

(136 citation statements)

References 53 publications

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“…2 A role of immune-mediated suppression of hematopoiesis has been most extensively defined in trisomy 8 MDS. Consistent with what was shown for the general population of MDS patients, 4,6,7 Sloand et al 5 have demonstrated that expanded clonal populations of T cells can be found in all patients with trisomy 8. In addition, they showed that the suppressive action of autologous T cells in these patients is restricted to CD8 þ T cells with this specific clonotype.…”

Section: Discussionsupporting

confidence: 73%

“…In trisomy 8 patients responding to immunosuppressive therapy, the number of progenitor cells with an extra chromosome 8 increases, 5 suggesting that the expanded clonal population of T lymphocytes in these patients controls the growth of genetically abnormal hematopoietic progenitors. Marrow failure associated with this immune response that appears to be directed specifically at the malignant clone, must therefore come from bystander effects on remaining normal hematopoietic cells.…”

Section: Discussionmentioning

confidence: 99%

“…2,3 Clonal and oligoclonal T cell expansions can be found in about half of the patients 2,4-7 and these clones have been shown to suppress hematopoiesis in vitro. 5 Compelling evidence for the effective role of T cells in the process of BM failure comes from the observation that up to 30% of low-risk MDS patients respond to immunosuppressive agents such as cyclosporine A (CsA), 8 and/or anti-thymocyte globulin (ATG) [9][10][11][12][13][14] which mainly target activated T cells.…”

Section: Introductionmentioning

confidence: 99%

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Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40–CD40L interactions with T helper cells

Meers

Kasran

Boon³

et al. 2007

Leukemia

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Immune mechanisms have been shown to contribute to the process of myelodysplastic syndromes (MDS)-related bone marrow (BM) failure. The aim of this study was to evaluate the possible contribution of activated monocytes through CD40-CD40L(CD154) interactions with activated T helper cells. We demonstrated in 77 predominantly lower risk MDS patients that the CD40 receptor was expressed significantly higher on monocytes and that CD40L was expressed significantly higher on T helper cells in peripheral blood (PB) and BM. Increased levels of CD40 and CD40L were detected in the same patients. In addition, stimulation of the CD40 receptor on purified PB monocytes led to a significantly higher tumor necrosis factor alpha production in patients. Co-culture of BM mononuclear cells of 21 patients in the presence of a blocking CD40 monoclonal antibody (ch5D12) led to a significant increase in the number of colony-forming units. A correlation was seen between increased CD40 expression on monocytes with patients' age below 60 years and with the cytogenetic abnormality trisomy 8. These results demonstrate that CD40 expression on monocytes may identify a subgroup of MDS patients in whom immune-mediated hematopoietic failure is part of the disease process. As such, the CD40-CD40L-based activation of monocytes might be a target to counteract MDS-related BM failure.

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40–CD40L interactions with T helper cells

Meers

Kasran

Boon³

et al. 2007

Leukemia

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“…Monosomy 7 and monosomy 20 are generally considered karyotypes associated with less immunogenicity and poorer prognosis than other cytogenetic abnormalities, especially when compared previously to patients with trisomy 8 mutations. 7,37 A cohort of 34 MDS patients with trisomy 8 were found to have extensive CD8 þ T-cell expansion that inhibited trisomy 8 positive myeloid colonies growth in vitro. 6,37 Of these 34 patients, 28 exhibited trisomy 8 as a sole mutation and an additional three patients displayed trisomy 8 in conjunction with either 5q-or monosomy 20.…”

Section: Discussionmentioning

confidence: 99%

“…36 The presence of an abnormal karyotype including trisomy 8, has been specifically linked to both response to immune suppression and the presence of clonal T cells. 6,37 Although the number of patients with each individual chromosome abnormality was small, all patients with monosomy 20 (3 out of 3) and most with monosomy seven (3 out of 4) had clonal T cells demonstrable in the peripheral blood (Table 2), whereas only one of four patients with trisomy 8 had clonal T-cell expansions.…”

Section: Clinical Characteristics Of Mds Patients With Clonal T Cellsmentioning

confidence: 99%

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome

et al. 2007

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Selected patients with Myelodysplastic Syndromes (MDS) are responsive to immunosuppressive therapy, suggesting that hematopoietic suppressive T cells have a pathogenic role in ineffective hematopoiesis. We assessed T-cell receptor (TCR) clonality through combined flow cytometry and molecular analysis of the complementarity determining region (CDR)-3 of the T-cell receptor-Vb gene. We identified clonal T cells in 50% of MDS patients (n ¼ 52) compared to 5% of age-matched normal controls (n ¼ 20). The presence of T-cell clones was not associated with features linked previously to immunosuppression response, including WHO diagnostic category, karyotype, marrow cellularity, IPSS category, sex or age p60. Using flow cytometry to identify expanded Vb-families, we found that T cells showed greater expansion in the bone marrow compared with peripheral blood, and were characterized as CD8 þ /CD57 þ /CD28 À effector T cells. Expanded effector T cell were CD62L negative and expressed the natural killer C-lectinfamily receptor NKG2D and CD244 (2B4). We conclude that clonal T-cell expansion is common among all MDS prognostic subgroups.

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Targeting Immune Dysregulation in Myelodysplastic Syndromes

Olnes¹

2011

JAMA

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Myelodysplastic syndromes (MDS) are a heterogeneous group of bone marrow disorders characterized by ineffective hematopoiesis and a tendency to develop leukemia. In some patients, laboratory and clinical evidence supports a role for the immune system in the pathogenesis of early MDS. Many younger patients who respond to immunosuppressive therapy with drugs such as antithymocyte globulin and cyclosporine have clonal expansions of cytotoxic CD8(+) T cells that suppress normal hematopoiesis, as well as expansion of CD4(+) helper T-cell subsets that promote and sustain autoimmunity. Immunosuppressive therapy can produce hematologic responses in some patients and may improve survival and halt leukemic progression. In this report, we describe a 56-year-old woman who presented with fatigue and easy bruising, eventually became pancytopenic, and was diagnosed with MDS. After treatment with a clinical protocol using alemtuzumab, an anti-CD52 antibody, her blood cell counts returned to normal and she has remained in complete remission for more than 2 years of follow-up. In this article, we review the pathobiology of immune dysregulation in MDS and summarize the role of immunosuppressive therapy in MDS.

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Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome

Cited by 163 publications

References 53 publications

Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40–CD40L interactions with T helper cells

Monocytes are activated in patients with myelodysplastic syndromes and can contribute to bone marrow failure through CD40–CD40L interactions with T helper cells

Prevalence and clinical association of clonal T-cell expansions in Myelodysplastic Syndrome

Targeting Immune Dysregulation in Myelodysplastic Syndromes

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