Mouse Models for Immune‐Mediated Platelet Destruction or Immune Thrombocytopenia (ITP)

Neschadim, Anton; Branch, Donald R.

doi:10.1002/0471142735.im1530s113

Cited by 13 publications

(18 citation statements)

References 55 publications

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“…In animal experiments, mice were treated with the anti‐α IIb antibody with or without injection of the anti‐α v antibody. As previously reported , anti‐α IIb antibody treatment alone decreased the platelet counts to a very low level. In this study, we showed that a longer duration of thrombocytopenia and slower recovery of the platelet level were observed in anti‐α IIb /anti‐α v antibody‐treated mice.…”

Section: Discussionsupporting

confidence: 85%

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Autoantibody against integrin αvβ3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes

Zeng

Chen

Wang

et al. 2018

Journal of Thrombosis and Haemostasis

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Background The pathogenesis of immune thrombocytopenia (ITP) has not been fully clarified. Anti-αvβ3 integrin autoantibody is detected in chronic ITP patients, but its contribution to ITP is still unclear. Objectives To clarify the potential role of anti-αvβ3 integrin autoantibody in chronic ITP and the related mechanism. Methods Relationship between levels of anti-αvβ3 autoantibody and platelets in chronic ITP patients was evaluated. The influence of anti-αvβ3 antibody on megakaryocyte (MK) survival, differentiation, migration and adhesion was assessed, and the associated signal pathways were investigated. Platelet recovery and MKs' distribution were observed in an ITP mouse model pretreated with different antibodies. Result In this study, we showed that the anti-αvβ3 autoantibody usually coexists with anti-αIIbβ3 autoantibody in chronic ITP patients, and patients with both autoantibodies have lower platelets. In in vitro studies, we showed that the anti-αvβ3 antibody had no significant effect on the survival and proliferation of MKs, whereas it decreased formations of proplatelet significantly. Anti-αvβ3 antibody impeded stromal cell derived facor-1 alpha (SDF-1α)- mediated migration and inhibited the phosphorylation of protein kinase B. Anti-αvβ3 antibody significantly inhibited MKs' adhesion to endothelial cells and Fibrogen. The phosphorylation of focal adhesion kinase and proto-oncogene tyrosine-protein kinase Src induced by adhesion was inhibited when MKs were pretreated with anti-αvβ3 antibody. In in vivo studies, we showed that injection with anti-α antibody delayed platelet recovery in a mouse model of ITP. Conclusions These findings demonstrate that the autoantibody against integrin α β may aggravate thrombocytopenia in ITP patients by impeding MK migration and adhesion to the vascular niche, which provides new insights into the pathogenesis of ITP.

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Section: Discussionsupporting

confidence: 85%

“…An ITP mouse model was generated by injection with the anti‐α IIb antibody (WMReg30) for 7 days (Fig. A), as previously described . Similarly, because α v integrin is the main domain of α v β 3 and targeting α v reduces the migration ability of certain cells , anti‐α v (CD51) antibody was applied in the in vivo experiment.…”

Section: Resultsmentioning

confidence: 99%

Autoantibody against integrin αvβ3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes

Zeng

Chen

Wang

et al. 2018

Journal of Thrombosis and Haemostasis

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“…Four weeks after HP inoculation, 2 μg of rat anti-mouse CD41 monoclonal antibody (BD Bioscience) diluted with 200 ul PBS was injected intraperitoneally into balb/c mice of the HP&ITP group and the ITP group for 5 consecutive days. 24 In addition, the normal control group was injected with 200 ul PBS daily for 5 days. Blood samples were taken from the caudal vein of the mice before each antibody injection.…”

Section: Methodsmentioning

confidence: 99%

Helicobacter pylori Regulates the Apoptosis of Human Megakaryocyte Cells via NF-κB/IL-17 Signaling

Lei

Tan

et al. 2021

OTT

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Objective: To investigate the role of Helicobacter pylori (HP) on the regulation of NF-κB/ IL-17 signaling, mechanisms underlying apoptosis in human megakaryocyte cell lines Dami. Methods: Firstly, the mouse model of immune thrombocytopenia (ITP) was established. Then, the mice were subjected to gastric perfusion with HP. Next, the changes in platelet and bone marrow megakaryocyte classification were assessed in each group. Human megakaryocyte Dami cells were treated with HP in vitro for 3, 6, or 9 h; and the rates of apoptosis in each group were then evaluated with flow cytometry. Fluorescent quantitative PCR and Western blotting were implemented for assessing the expression of Bcl-2 and Bax, which are related to apoptosis, and p65, which is associated with the NF-κB pathway. The expression of these proteins was also evaluated after treatment with PDTC, an inhibitor of the NF-κB pathway inhibitor. Results: In vivo, exogenous administration of HP was found to increase the optical density value for the anti-HP antibody in HP-infected BALB/c mice. Meanwhile, the platelet counts in the HP-infected ITP mice model were significantly reduced compared with non-infected ITP mice. In vitro, the apoptotic rate of Dami cells increased gradually with the prolongation of the exposure to HP; the most noticeable change was at 6 h, and there was a significant difference between 0 h and 6 h. The expression of Bax, p-p65, and IL-17 also increased progressively with the prolongation HP exposure, while the expression of anti-apoptotic Bcl-2 protein decreased gradually, especially at 6 h, and the expression of total p65 did not change significantly compared with baseline. Anecdotally, these effects were reversed by the application of pyrrolidine dithiocarbamate (PDTC), an inhibitor of NF-κB signaling. Conclusion: HP can promote platelet destruction in ITP mice, and the underlying mechanisms may be related to accelerating apoptosis of megakaryocytes by the activation of the NF-κB/IL-17 pathway.

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“…IL-11 is not detected in the blood of healthy humans or mice at steady state. Nevertheless, several studies demonstrate that IL-11 over-production is induced by IVIg in experimental mouse models of autoimmune encephalitis and ITP [11][12][13][14]. IL-11 exhibits anti-inflammatory effects and even exerts a beneficial effect on tissue myelin repair in mice [9,15,16].…”

Section: Introductionmentioning

confidence: 99%

IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans

Nguyen¹,

Repessé²,

Ebbo

et al. 2021

Clinical and Experimental Immunology

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The mechanisms of action of intravenous immunoglobulins (IVIg) in autoimmune diseases are not fully understood. The fixed duration of efficacy and noncumulative effects of IVIg in immune thrombocytopenia (ITP) and acquired von Willebrand disease (AVWD) suggest other mechanisms besides immunological ones. Additionally to the peripheral destruction of platelets in ITP, their medullary hypoproduction emerged as a new paradigm with rescue of thrombopoietin receptor agonists (TPO-RA). In an ITP mouse model, interleukin (IL)-11 blood levels increase following IVIg. IL-11 stimulates the production of platelets and other haemostasis factors; recombinant IL-11 (rIL-11) is thus used as a growth factor in postchemotherapy thrombocytopenia. We therefore hypothesized that IVIg induces IL-11 over-production, which increases platelets, VWF and factor VIII (FVIII) levels in humans and mice. First, in an ITP mouse model, we show that IVIg or rIL-11 induces a rapid increase (72 h) in platelets, FVIII and VWF levels, whereas anti-IL-11 antibody greatly decreased this effect. Secondly, we quantify for the first time in patients with ITP, AVWD, inflammatory myopathies or Guillain-Barré syndrome the dramatic IL-11 increase following IVIg, regardless of the disease. As observed in mice, platelets, VWF and FVIII levels increased following IVIg. The late evolution (4 weeks) of post-IVIg IL-11 levels overlapped with those of VWF and platelets. These data may explain thrombotic events following IVIg and open perspectives to monitor post-IVIg IL-11/thrombopoietin ratios, and to assess rIL-11 use with or without TPO-RA as megakaryopoiesis co-stimulating factors to overcome the relative hypoproduction of platelets or VWF in corresponding autoimmune diseases, besides immunosuppressant.

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Mouse Models for Immune‐Mediated Platelet Destruction or Immune Thrombocytopenia (ITP)

Cited by 13 publications

References 55 publications

Autoantibody against integrin αvβ3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes

Autoantibody against integrin αvβ3 contributes to thrombocytopenia by blocking the migration and adhesion of megakaryocytes

Helicobacter pylori Regulates the Apoptosis of Human Megakaryocyte Cells via NF-κB/IL-17 Signaling

IVIg increases interleukin-11 levels, which in turn contribute to increased platelets, VWF and FVIII in mice and humans

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