Proliferation and apoptosis of bone marrow CD4+ T cells in patients with aplastic anemia and impacts of the secreted cytokines on hematopoietic stem cells from umbilical cord blood

Zheng, Ming; Sun, Han‐Dong; Zhou, Jianfeng; Xu, Huibi; Huang, Lifang; Liu, Wenli

doi:10.1007/s11596-010-0107-3

Cited by 7 publications

(3 citation statements)

References 23 publications

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“…Myeloma is a heterogenetic hematological malignancy with characteristic tumor-induced angiogenesis, which is different from other hematologic disease, such as aplastic anemia [33] . Clinically, myeloma patients respond differently to anti-angiogenesis drugs, such as thalidomide.…”

Section: Discussionmentioning

confidence: 99%

P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells

Shao

Wang

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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P-450-dependent epoxygenase pathway of arachidonic acid and the products of epoxyeicosatrienoic acids (EETs) have been demonstrated to be involved in angiogenesis and tumor progression. This study examined the expression of EETs and the role of the pathway in the angiogenesis of multiple myeloma (MM). MM cell lines of U266 and RPMI8226 were cultured, and the EETs levels (11, 12-EET and 14, 15-EET) in the supernatant were determined by ELISA. Human umbilical vein endothelial cells (HUVECs) were cultured and used for analysis of the angiogenesis activity of the two MM cell lines, which was examined both in vitro and in vivo by employing MTT, chemotaxis, tube formation and matrigel plug assays. 11, 12-EET and 14, 15-EET were found in the supernatant of the cultured MM cells. The levels of the two EETs in the supernatant of U266 cells were significantly higher than those in the RPMI8226 cell supernatant (P<0.05), and the levels paralleled the respective angiogenesis activity of the two different MM cell lines. 17-octadecynoic acid (17-ODYA), as a specific inhibitor of P450 enzyme, suppressed HUVECs proliferation and tube formation induced by MM cells. Furthermore, 17-ODYA decreased the EET levels in the supernatant of MM cells. These results suggest that EETs may play an important role in the angiogenesis of MM, and the inhibitor 17-ODYA suppresses this effect.

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Section: Discussionmentioning

confidence: 99%

P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells

Shao

Wang

et al. 2011

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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“…Culture supernatants obtained from the proliferation and suppression assays were added at a ratio of 1:4. 26 Colonies were enumerated 14 days after incubation. …”

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confidence: 99%

Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

Shi

et al. 2012

Blood

118

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IntroductionAcquired aplastic anemia (AA), characterized by pancytopenia in peripheral blood (PB) and bone marrow (BM) hypoplasia, is a bone marrow failure syndrome attacked by autologous T cells, such as CD8 ϩ cytotoxic T cells, CD4 ϩ Th1 cells, and Th17 cells, on BM hematopoietic progenitors. [1][2][3][4] Hematopoiesis recovery after successful immunosuppressive treatment provided powerful evidence for the core role of the immune-mediated destruction of hematopoietic progenitor/stem cells. Mechanisms of immunemediated destruction of hematopoiesis include Th1 polarization response conferring immoderate production of inhibitory cytokines such as interferon-␥ (IFN-␥), tumor necrosis factor-␣ (TNF-␣), and interleukin-2 (IL-2), direct toxicity to autologous CD34 ϩ cells by T-cell populations, and Th17 immune response. [4][5][6][7] In that sense, AA is a specific autoimmune disease because of aberrant T-cell immune homeostasis and BM is the main target organ.It is now well established that CD4 ϩ T-cell subpopulations constitutively expressing the surface protein CD25 and the transcription factor FoxP3 are indispensable for the maintenance of immunologic self-tolerance and immunosuppression. [8][9][10][11] There is also accumulating evidence that impaired function of CD4 ϩ CD25 ϩ regulatory T cells (Tregs) has been implicated in the development of several common autoimmune diseases, 8,10 myelodysplastic syndromes, 12 and AA. 13 Until now, the only report of Treg abnormality in AA has shown that the numbers of circulating Tregs decreased in most patients. Meanwhile, almost all patients had low levels of nuclear factor of activated T cells, cytoplasmic 2 (NFAT1/ NFATc2) which could explain decreased FoxP3 expression in Tregs from AA patients. 13 But little is known regarding the function of Tregs in AA.Physiologically, induction of immune tolerance and suppression of autoreactive effector T-cell proliferation were the critical function of CD4 ϩ CD25 ϩ Tregs through cell contact-inhibition mechanisms and/or production of inhibitory cytokine. Furthermore, BM is a reservoir for CD4 ϩ CD25 ϩ Tregs that home to and are retained in BM through the stromal-derived factor-1␣ (SDF-1␣)/ CXCR4 signal. 14 Previous data demonstrated that the only way for Tregs homing to BM was via the SDF-1␣/CXCR4 signal. 14,15 It was believed that CXCR4 was the only receptor of SDF-1␣ for years. However, several reports recently provided evidence that SDF-1␣ also bound to another 7 transmembrane span receptor CXCR7. 16,17 Thus, the role of the SDF-1␣/CXCR4 axis in regulating Treg trafficking between BM and PB becomes more complex. Combined with the fact that BM is the target organ attacked by autoreactive effector T cells leading to hematopoiesis destruction, we hypothesized that Tregs in AA might have impaired homing potential to BM so as to be less efficient to suppress the effector T-cell proliferation and Th1-type cytokine production. We also hypothesized that Tregs in AA had intrinsic deficiencies of immunosuppression for autologous effector T...

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“…More recent study found that some AA patients have an increased CD4/CD8 T cell ratio in the course of the disease [13]. Studies of T cell clonality and function through T cell receptor beta variable region classification [14], spectrotyping [15], gene expression array analyses [16], and cell apoptosis assays [17,18], also implicated CD4 T cells in human marrow failure. In murine models, depletion of CD4 T cells abrogated the ability of allogeneic lymphocytes to induce marrow damage, supporting the idea that CD4 T cells also play some role in immune-mediated BM failure [19].…”

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confidence: 99%

MHC class II upregulation and colocalization with Fas in experimental models of immune-mediated bone marrow failure

Erie

Samsel

Takaku

et al. 2011

Experimental Hematology

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Objective To test the hypothesis that gamma interferon (IFN-γ) promotes MHC class II expression on bone marrow (BM) cell targets that facilitates T cell-mediated BM destruction in immune-mediated BM failure. Materials and Methods Allogeneic lymph node (LN) cells were infused into MHC or minor histocompatibility antigen (minor-H) mismatched hosts to induce BM failure. MHC class II and Fas expression and cell apoptosis were analyzed by flow cytometry. MHC class II-Fas co-localization was detected by ImageStream Imaging Flow Cytometry and other cell-cell associations were visualized by confocal microscopy. T cell-mediated BM cell apoptosis and effects of IFN-γ on MHC class II-Fas co-localization on normal BM cells were studied using cell culture in vitro followed by conventional and imaging flow cytometry. Results BM failure animals had significantly up-regulated MHC class II expression on CD4−CD8−CD11b−CD45R− residual BM cells and significantly increased MHC class II-Fas co-localization on BM CD150+ and CD34+ hematopoietic cells. MHC class II+Fas+ BM cells were closely associated with CD4+ T cells in the BM of affected animals, and they were significantly more responsive to T-cell mediated cell apoptosis relative to MHC class II−Fas− BM cells. Infusion of IFN-γ-deficient LN cells into minor-H mismatched recipients resulted in no MHC class II-Fas up-regulation and no clinically overt BM failure. Treatment with recombinant IFN-γ significantly increased both MHC class II-Fas co-expression and co-localization on normal BM cells. Conclusion Elevation of the inflammatory cytokine IFN-γ stimulated MHC class II expression and MHC class II-Fas co-localization, which may facilitate T-cell mediated cell destruction.

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Proliferation and apoptosis of bone marrow CD4+ T cells in patients with aplastic anemia and impacts of the secreted cytokines on hematopoietic stem cells from umbilical cord blood

Cited by 7 publications

References 23 publications

P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells

P-450-dependent epoxygenase pathway of arachidonic acid is involved in myeloma-induced angiogenesis of endothelial cells

Intrinsic impairment of CD4+CD25+ regulatory T cells in acquired aplastic anemia

MHC class II upregulation and colocalization with Fas in experimental models of immune-mediated bone marrow failure

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