Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia

Notch signalling is involved in the development of several autoimmune diseases, one of such diseases is ITP. The aim of this study was to investigate and compare the expression levels of Notch1 receptor and its target Hes1 gene in Egyptian paediatric ITP patients. Real-time quantitative reverse transcriptase polymerase chain reaction was used to analyse the expression levels of Notch1 and Hes1 in 42 children with primary ITP (22 newly diagnosed and 20 persistent) cases. Twenty age and sex matched non-ITP controls were included. The expression levels of Notch1 were higher in newly diagnosed and persistent cases than controls with high statistical significant difference (P value \ 0.001, P \ 0.001) respectively, similarly as regards the expression levels of HES1 (P value \ 0.001, P \ 0.007) respectively. A significant positive correlation was found between Notch1 and Hes1 expression levels in newly diagnosed cases (r = 0.587, P value = 0.004). There was an association between levels of both genes in most of ITP patients but Hes1 was markedly elevated than Notch1 in few cases. High expression levels of Notch1/Hes1 indicated the important role of Notch signalling in both newly diagnosed and persistent ITP. High expression levels of Hes1 than Notch1 may shed light on its value as a therapeutic target for future research in ITP.

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“…High expression levels of Notch1/Hes1 presented in our study were similar to those reported in other autoimmune diseases [34][35][36][37].…”

Section: Discussionsupporting

confidence: 91%

Correlation of Notch1/Hes1 Genes Expression Levels in Egyptian Paediatric Patients with Newly Diagnosed and Persistent Primary Immune(Idiopathic) Thrombocytopenic Purpura

Gawdat

Hammam

Ezzat

2015

Indian J Hematol Blood Transfus

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“…One mechanism by which Notch signaling could have impacted SLEC differentiation is via its ability to regulate T-bet expression. Indeed, Tbx21 has been reported to be a direct transcriptional target of Notch in CD4 + T cells (14,15). In CD8 + T cells, inhibition of Notch signaling following in vitro stimulation of CD8 + T cells leads to reduced expression of T-bet, but, unfortunately, the direct binding of the NICD to the Tbx21 gene was not evaluated in this study (23).…”

Section: Discussionmentioning

confidence: 90%

“…Moreover, there is evidence that Tbx21 is a Notch target gene (14,15,23). Therefore, we evaluated whether the reduced generation of SLECs in the absence of Notch1/2 correlated with a decrease in T-bet expression.…”

Section: Defective Slec Generation Is Not the Consequence Of Reduced mentioning

confidence: 99%

“…This initial observation has now been expanded to the differentiation of several Th cell subsets (12). Specifically, the Notch signaling pathway was shown to directly regulate the transcription of Tbx21 (encoding for T-bet) and to increase IFN-g production in Th1 cells (14,15). The Notch pathway is also a direct regulator of Gata3 transcription during Th2 differentiation (16,17).…”

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confidence: 97%

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The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

Mathieu

Duval

Daudelin

et al. 2015

The Journal of Immunology

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Following an infection, naive CD8+ T cells expand and differentiate into two main populations of effectors: short-lived effector cells (SLECs) and memory precursor effector cells (MPECs). There is limited understanding of the molecular mechanism and cellular processes governing this cell fate. Notch is a key regulator of cell fate decision relevant in many immunological pathways. In this study, we add to the role of Notch in cell fate decision and demonstrate that the Notch signaling pathway controls the MPEC/SLEC differentiation choice following both Listeria infection and dendritic cell immunization of mice. Although fewer SLECs were generated, Notch deficiency did not alter the rate of memory CD8+ T cell generation. Moreover, we reveal that the Notch signaling pathway plays a context-dependent role for optimal cytokine production by effector CD8+ T cells. Together, our results unravel critical functions for the Notch signaling pathway during effector CD8+ T cell differentiation.

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“…However, interpretation was difficult given possible non-cellautonomous effects of overexpressed Notch ligands, the lack of direct genetic demonstration, and the artificial nature of the gain-of-function experimental systems. More recently, several laboratories used in vivo loss-of-function strategies to evaluate the role of Notch signaling in alloimmunity (41,(117)(118)(119)(120)(121)(122)(123)139). These studies reached concordant conclusions that Notch functions as a major proinflammatory signaling pathway promoting pathogenic alloreactivity, in both GVHD and transplant rejection.…”

Section: Early Insights On Notch Signaling In Alloimmunitymentioning

confidence: 99%

New Insights into Graft-Versus-Host Disease and Graft Rejection

Perkey

Maillard

2018

Annu. Rev. Pathol. Mech. Dis.

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Allogeneic transplantation of foreign organs or tissues has lifesaving potential, but can lead to serious complications. After solid organ transplantation, immune-mediated rejection mandates the use of prolonged global immunosuppression and limits the life span of transplanted allografts. After bone marrow transplantation, donor-derived immune cells can trigger life-threatening graft-versus-host disease. T cells are central mediators of alloimmune complications and the target of most existing therapeutic interventions. We review recent progress in identifying multiple cell types in addition to T cells and new molecular pathways that regulate pathogenic alloreactivity. Key discoveries include the cellular subsets that function as potential sources of alloantigens, the cross talk of innate lymphoid cells with damaged epithelia and with the recipient microbiome, the impact of the alarmin interleukin-33 on alloreactivity, and the role of Notch ligands expressed by fibroblastic stromal cells in alloimmunity. While refining our understanding of transplantation immunobiology, these findings identify new therapeutic targets and new areas of investigation.

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Therapeutic targeting of NOTCH signaling ameliorates immune-mediated bone marrow failure of aplastic anemia

Abstract: Notch1 signaling sustains the proinflammatory behavior of Th1 cells, implicated in the development of aplastic anemia in humans and mice.

Cited by 67 publications

References 61 publications

Correlation of Notch1/Hes1 Genes Expression Levels in Egyptian Paediatric Patients with Newly Diagnosed and Persistent Primary Immune(Idiopathic) Thrombocytopenic Purpura

Correlation of Notch1/Hes1 Genes Expression Levels in Egyptian Paediatric Patients with Newly Diagnosed and Persistent Primary Immune(Idiopathic) Thrombocytopenic Purpura

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

New Insights into Graft-Versus-Host Disease and Graft Rejection

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