Regulatory T-cells in Acquired Aplastic Anaemia (original) (raw)
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Identification of novel regulators in T-cell differentiation of aplastic anemia patients
BMC genomics, 2006
Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR. Among more than 22,200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candid...
Experimental Hematology, 2005
Patients and Methods. We studied bone marrow MSC from 19 healthy donors and 23 SAA patients in different phases of the disease: at diagnosis (n ϭ 3), following immunosuppressive therapy (IS) (n ϭ 16), or after a bone marrow transplant (BMT) (n ϭ 4). MSC were tested for T-cell suppression in the following assays: mixed lymphocyte reaction (MLR), phytohemaglutinin (PHA)-primed cultures, activation surface markers, g-IFN production, hematopoietic colony formation (CFC), production of cyclic ADP-ribose (cADPR).
Analysis at the clonal level of T-cell phenotype and functions in severe aplastic anemia patients
Blood, 1991
The aim of this study was to analyze at the clonal level the phenotype and functions of T cells from patients with severe aplastic anemia (SAA). For this purpose we studied 175 T-cell clones obtained from peripheral blood (PB) and bone marrow (BM) of four SAA patients and 97 clones from two healthy controls. The percentage of CD8+ T-cell clones obtained from the patients' PB and BM was higher, but not significantly (P = .07 and P = .14, respectively), than that obtained in controls. A higher proportion of T-cell clones from SAA patients exhibited lectin-dependent cytolytic activity and especially natural killer-like activity when compared with controls (PB: P less than .01, P less than .05; BM: P less than .05, P less than .01, respectively). Lymphokine release was tested before and after mitogen stimulation. A number of patients' clones were able to release interferons (IFNs) spontaneously (PB: 28.6% v 0%, P less than .05; BM: 28.6% v 0%, P less than .10). After mitogen sti...
Functional characterization of CD4+ T cells in aplastic anemia
Blood, 2012
The role of CD4 ؉ T cells in the pathogenesis of aplastic anemia (AA) is not well characterized. We investigate CD4 ؉ T-cell subsets in AA. Sixty-three patients with acquired AA were studied. Th1 and Th2 cells were significantly higher in AA patients than in healthy donors (HDs; P ؍ .03 and P ؍ .006). Tregs were significantly lower in patients with severe AA than in HDs (P < .001) and patients with nonsevere AA (P ؍ .01). Th17 cells were in-creased in severe AA (P ؍ .02) but normal in non-severe AA. Activated and resting Tregs were reduced in AA (P ؍ .004; P ؍ .01), whereas cytokine-secreting non-Tregs were increased (P ؍ .003). Tregs from AA patients were unable to suppress normal effector T cells. In contrast, AA effector T cells were suppressible by Tregs from HDs. Th1 clonality in AA, investigated by high-throughput sequencing, was greater than in HDs (P ؍ .03).
Experimental Hematology, 2004
Objective. Immune-mediated destruction of hematopoietic stem and progenitor cells is pathophysiologic in most cases of aplastic anemia (AA). We have successfully determined the gene expression profile of the marrow CD34 ϩ target cells in AA. T cells producing IFN-g and TNF-a have been implicated in hematopoietic destruction in AA. We sought to characterize T cells as immune mediators using the microarray approach. Materials and Methods. We applied Affymetrix GeneChip techniques to determine the detailed profile of mRNA expression of CD4 ϩ and CD8 ϩ cells from the BM of newly diagnosed AA patients and healthy volunteers. For validation, we confirmed our microarray results using quantitative real-time PCR.
Deficit of Circulating CD19+CD24hiCD38hi Regulatory B Cells in Severe Aplastic Anemia
Blood, 2019
Background: Immune aplastic anemia (AA) is caused by cytotoxic T cells (CTLs) that destroy hematopoietic stem and progenitor cells. Regulatory T cells (Tregs) are reduced in AA and increase in response to immunosuppressive therapy (IST; Solomou E et al, Blood 2007). Recent studies suggested an immune regulatory role of regulatory B cells (Bregs). Human CD19+CD24hiCD38hi Bregs suppress Th1 response of CD4+ T cells as well as IFN-γ production by CD8+ CTLs (Mauri C, Menon M, J Clin Invest 2017). The quantity and/or function of Bregs are impaired in autoimmune diseases, malignancies, chronic graft-versus-host disease, and during rejection of transplanted organs. Methods: We investigated B cell phenotypes including CD24hiCD38hi Bregs in previously untreated severe AA (SAA) and very severe AA (VSAA) patients, and healthy individuals aged 18 years and older, and tested their correlation with severity and response to IST. Absolute numbers of lymphocyte subsets, including CD19+ B cells, CD8+...
Acute Lymphoblastic Leukemia and Regulatory T cells: Biomarkers and Immunopathogenesis
Current Immunology Reviews, 2015
Acute Lymphoblastic Leukemia (ALL) is a hematological malignancy and the most prevalent form of childhood leukemia. Development of ALL is related to the blockade of lymphocyte differentiation, which might affect B or T precursor cells, resulting in the accumulation of blasts in bone marrow. Moreover, immunopathogenesis of ALL involves T regulatory cells (Tregs), which have been investigated in leukemic patients, presenting more immunosuppressive ability than those from normal individuals. Tregs are critical for the maintenance of autoreactive cells, affecting both lineages CD4+ and CD8+, and immune vigilance. Evaluating the role of Tregs in ALL is possible by determining biomarkers related to these cells, such as FOXP3, CD25, CTLA-4 and other molecules that contribute to immunoregulation. In this context, leukemic cells produce ligands that recruit Tregs to the marrow microenvironment, suppressing the antitumor immune response and supporting cancer development. Overall, although Tregs are necessary to inhibit autoreactive T cells, the excessive stimulation of these cells leads to an immunosuppressive state. Immunosuppression in ALL may be partially attributed to the indirect effect of blast cells, which recruit and allow Treg cells to expand, as well as to increase immunosuppressive molecules secreted by both cells. The involvement of Tregs in the immunopathogenesis and their implications in ALL are under the scope of this review and may have important implications in the future.