Inhibitory effects of tumor necrosis factor on hematopoiesis seen in vitro are translated to increased numbers of both committed and multipotent progenitors in TNF-deficient mice

Drutskaya, Marina S.; Ortiz, Mariestela; Liepinsh, Dmitry J.; Kuprash, Dmitry V.; Nedospasov, Sergei A.; Keller, Jonathan R.

doi:10.1016/j.exphem.2005.08.001

Cited by 14 publications

(15 citation statements)

References 34 publications

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“…Moreover, in vitro exposure to supernatants from irradiated BM stroma, treated or untreated with a neutralizing antibody to TNF-α, demonstrated the TNF-α released in response to irradiation is partially responsible for BM cell apoptosis induction. Other studies have highlighted the role of TNF-α signalling in hematopoietic progenitor turnover in vitro [22]–[24]. Accordingly, we demonstrate in vivo thatWT mice treated with anti-TNF-α Ab as well TNF-α deficient mice were more resistant to irradiation-induced BM cell turnover than non-treated WT mice.…”

Section: Discussionsupporting

confidence: 62%

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

et al. 2010

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BackgroundSecondary bone marrow (BM) myelodysplastic syndromes (MDS) are increasingly common, as a result of radio or chemotherapy administered to a majority of cancer patients. Patients with secondary MDS have increased BM cell apoptosis, which results in BM dysfunction (cytopenias), and an increased risk of developing fatal acute leukemias. In the present study we asked whether TNF-α, known to regulate cell apoptosis, could modulate the onset of secondary MDS.Principal FindingsWe show that TNF-α is induced by irradiation and regulates BM cells apoptosis in vitro and in vivo. In contrast to irradiated wild type (WT) mice, TNF-α deficient (TNF-α KO) mice or WT mice treated with a TNF-α-neutralizing antibody were partially protected from the apoptotic effects of irradiation. Next we established a 3-cycle irradiation protocol, in which mice were sub-lethally irradiated once monthly over a 3 month period. In this model, irradiated WT mice presented loss of microsatellite markers on BM cells, low white blood cell (WBC) counts, reduced megakaryocyte (MK) and platelet levels (thrombocytopenia) and macrocytic anemia, phenoypes that suggest the irradiation protocol resulted in BM dysfunction with clinical features of MDS. In contrast, TNF-α KO mice were protected from the irradiation effects: BM cell apoptosis following irradiation was significantly reduced, concomitant with sustained BM MK numbers and absence of other cytopenias. Moreover, irradiated WT mice with long term (≥5 months) BM dysfunction had increased BM angiogenesis, MMPs and VEGF and NFkB p65, suggestive of disease progression.ConclusionTaken together, our data shows that TNF-α induction following irradiation modulates BM cell apoptosis and is a crucial event in BM dysfunction, secondary MDS onset and progression.

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Section: Discussionsupporting

confidence: 62%

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

et al. 2010

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“…Interactions with adjacent cells and with marrow stroma essentially substitute for very high concentrations of soluble cytokines within the hematopoietic niche, where hematopoietic cells are submitted to regulation [47] within highly organized system of hematopoietic niches in the marrow [48]. It is uncertain from the present data whether membrane bound or soluble TNF-a released by marrow stroma [46], hematopoietic cells [49], or immune cells [22,24] affect hematopoietic cell function under transplant conditions. The low concentrations of soluble TNF-a measured in the marrow space after transplantation suggest that the bound ligand operates as an autocrine or paracrine signaling pathway.…”

Section: Discussioncontrasting

confidence: 50%

“…Activation-induced cell death is mediated in immune cells both by soluble TNF-a [44] and by membrane-bound TNF-a through more selective interaction with TNF-R2 [45]. TNF signaling mediates interactions of hematopoietic cells with other cell types, such as sensitization to apoptosis by NK cells [24], reduced clonogenic activity in long-term cultures [46] and support of engraftment by plasmacytoid dendritic cells [22]. Interactions with adjacent cells and with marrow stroma essentially substitute for very high concentrations of soluble cytokines within the hematopoietic niche, where hematopoietic cells are submitted to regulation [47] within highly organized system of hematopoietic niches in the marrow [48].…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor Receptors Support Murine Hematopoietic Progenitor Function in the Early Stages of Engraftment

Pearl‐Yafe¹,

Mizrahi

Stein³

et al. 2010

Stem Cells

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Tumor necrosis factor (TNF) family receptors/ligands are important participants in hematopoietic homeostasis, in particular as essential negative expansion regulators of differentiated clones. As a prominent injury cytokine, TNF-a has been traditionally considered to suppress donor hematopoietic stem and progenitor cell function after transplantation. We monitored the involvement of TNF receptors (TNF-R) 1 and 2 in murine hematopoietic cell engraftment and their inter-relationship with Fas. Transplantation of lineage-negative (lin 2 ) bone marrow cells (BMC) from TNF receptor-deficient mice into wild-type recipients showed defective early engraftment and loss of durable hematopoietic contribution upon recovery of host hematopoiesis. Consistently, cells deficient in TNF receptors had reduced competitive capacity as compared to wild-type progenitors. The TNF receptors were acutely upregulated in bone marrow (BM)-homed donor cells (wild-type) early after transplantation, being expressed in 60%-75% of the donor cells after 6 days. Both TNF receptors were detected in fast cycling, early differentiating progenitors, and were ubiquitously expressed in the most primitive progenitors with long-term reconstituting potential (lin 2 ckit). BM-homed donor cells were insensitive to apoptosis induced by TNF-a and Fasligand and their combination, despite reciprocal inductive cross talk between the TNF and Fas receptors. The engraftment supporting effect of TNF-a is attributed to stimulation of progenitors through TNF-R1, which involves activation of the caspase cascade. This stimulatory effect was not observed for TNF-R2, and this receptor did not assume redundant stimulatory function in TNFR1-deficient cells. It is concluded that TNF-a plays a tropic role early after transplantation, which is essential to successful progenitor engraftment.

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“…We then assessed variations in the serum levels of cytokines involved in B-cell and granulocyte homeostasis: SDF-1 involved in human B-cell homeostasis and granulopoiesis, 8 TSLP involved in murine B-cell homeostasis and granulopoiesis, 9 TNF-alpha which inhibits granulopoiesis 10 and IL-6 which exhibits stimulatory effect on granulocyte production. 11,12 No fluctuations of TNF-alpha, TSLP and SDF-1 in serum were detected (Figure 2A, 2B, 2C, 2D).…”

Section: Resultsmentioning

confidence: 99%

Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery

Terrier¹,

Ittah²,

Tourneur³

et al. 2007

Haematologica

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Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recoveryRituximab is used in the treatment of lymphoma and autoimmune diseases, for which late-onset neutropenia (LON) were reported. LON-related mechanisms remain unclear. To obtain insights into the mechanisms, we assessed serum, peripheral blood and bone marrow (BM) samples of a patient with LON. Factors classically associated with neutropenia such as anti-neutrophil antibodies, T-LGL, soluble Fas Ligand were not detectable. We then evaluated the kinetics of various cytokines involved in B-cell and granulocyte homeostasis. We found that LON is related to a lack of granulopoiesis in the BM that coincides with a very high level of BAFF, a strong stimulator of B-cell recovery, and hypothesized a hematopoietic lineage competition due to an excessive B-cell recovery in the BM by promotion of B-cell lymphopoiesis over granulopoiesis within common developmental niches. Assessment of serum BAFF levels following rituximab could detect patients at risk of developing LON.Haematologica 2007; 92:(2)e20-e23 IntroductionRituximab, an anti-CD20 monoclonal antibody, is increasingly used in the treatment of lymphoma and autoimmune diseases. CD20 is expressed on malignant B-cells, normal differentiated B-cells and pre-B-cells, but not on stem cells and granulocyte precursors. Late-onset neutropenia following rituximab (LON) have been reported, 1-7 occurring 1 to 6 months after last rituximab infusion, as being severe (<0.5x10 9 /L), spontaneously reversible and without life-threatening infections.Several studies suggest that LON could be related to an excess of T-Large Granular Lymphocyte (LGL) in the bone marrow (BM) and peripheral blood (PB) which express and secrete large amounts of Fas and Fas Ligand (FasL) leading to apoptosis of mature neutrophils, 4 or to a production of autoantibodies binding to the neutrophil surface during recovery of a new immune repertoire. 2,6 On the other hand, a recent study suggests that LON is not related to circulating factors but to perturbations of Stromal-derived Factor 1 (SDF-1) and granulopoiesis homeostasis during B-cell recovery.7 This is reinforced by previous studies showing the hypocellularity of the marrow at the time of LON [1][2][3]6 and the absence of anti-neutrophil antibodies in the serum or T-LGL in the PB., 2,6,7 We report here that LON is related to a lack of granulopoiesis in the BM that coincides with the time of maximum B-cell depletion in PB, and proposed the hypothesis that LON is due to a hematopoietic lineage competition in the BM by promotion of B-cell lymphopoiesis over granulopoiesis within common developmental niches. Study designCase report. /L). At admission on day 84, blood tests revealed a severe neutropenia (0.2x10 9 /L), with normal hemoglobin level and platelet count, but the exact time from last treatment to the development of neutropenia could not be precisely determined with the available data. The serum monoclonal component...

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Inhibitory effects of tumor necrosis factor on hematopoiesis seen in vitro are translated to increased numbers of both committed and multipotent progenitors in TNF-deficient mice

Cited by 14 publications

References 34 publications

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

TNF-α Regulates the Effects of Irradiation in the Mouse Bone Marrow Microenvironment

Tumor Necrosis Factor Receptors Support Murine Hematopoietic Progenitor Function in the Early Stages of Engraftment

Late-onset neutropenia following rituximab results from a hematopoietic lineage competition due to an excessive BAFF-induced B-cell recovery

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