Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis

Ponsoye, Matthieu; Frantz, Camélia; Ruzehaji, Nadira; Nicco, Carole; Elhaï, Muriel; Ruiz, Barbara; Cauvet, Anne; Pezet, Sonia; Brandely, M; Batteux, Frédéric; Allanore, Yannick; Avouac, Jérôme

doi:10.1136/annrheumdis-2015-208213

Cited by 61 publications

(45 citation statements)

References 39 publications

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“…This result is supported by a recent study demonstrating that endothelial PI3Kβ promotes endothelial repair in vivo [55]. PI3Kβ is composed of a p110 catalytic and a p85 regulatory subunit, the latter being activated by tyrosine kinase receptors [56], however this kinase seems to be preferentially activated downstream of GPCR activation [36].…”

Section: Discussionsupporting

confidence: 71%

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Castaing-Berthou¹,

Malet²,

Radojkovic³

et al. 2017

Cell Physiol Biochem

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Background/Aims: High-density lipoproteins (HDL) exert multiple cardioprotective functions on the arterial wall, including the promotion of endothelial cell survival and proliferation. Among mechanism contributing to endothelial protection, it has been reported that apolipoprotein A-I (apoA-I), the major protein in HDL, binds and activates the endothelial ecto-F₁-ATPase receptor. This generates extracellular ADP, which in turn promotes endothelial cell survival. In this study we aimed to further investigate the signaling pathway involved downstream of apoA-I-induced ecto-F₁-ATPase activation. Methods: In human umbilical vein endothelial cells (HUVECs), pharmacological and gene silencing approaches were used to study pathways involved downstream ecto-F₁-ATPase activation by apoA-I. Results: ApoA-I and HDL both induced Akt phosphorylation. F₁-ATPase inhibitors such as inhibitory factor 1 and oligomycin completely blocked apoA-I-induced Akt phosphorylaton and significantly blocked HDL-induced phosphorylation, indicating that this signaling pathway is dependent on ecto-F₁-ATPase activation by apoA-I. Further, we were able to specify roles for the P2Y₁-ADPreceptor and the PI3Kβ isoform in this pathway since pharmacological inhibition and silencing of these proteins dramatically inhibited apoA-I-induced Akt phosphorylation and cell proliferation. Conclusion: Altogether, these data highlight a key role of the P2Y₁/PI3Kβ axis in endothelial cell proliferation downstream of ecto-F₁-ATPase activation by apoA-I. Pharmacological targeting of this pathway could represent a promising approach to enhance vascular endothelial protection.

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Section: Discussionsupporting

confidence: 71%

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Castaing-Berthou¹,

Malet²,

Radojkovic³

et al. 2017

Cell Physiol Biochem

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“…However, abatacept did not have any efficacy reducing dermal fibrosis in Tsk-1 mice (inflammatory-independent mouse model of SSc) reinforcing the concept that inhibition of T-cell response by abatacept can only prevent and reduce inflammation-driven dermal fibrosis. Moreover, abatacept did not protect against bleomycin-induced dermal fibrosis in CB17-SCID mice, further supporting the idea that T-cells have a role in the anti-fibrotic effect of abatacept [48]. Some case reports and observational studies have shown the benefit of abatacept in SSc patients.…”

Section: T-cellssupporting

confidence: 53%

Biological Therapy in Systemic Sclerosis

Caetano¹,

Oliveira²,

Alves³

2017

Systemic Sclerosis

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Systemic sclerosis is the autoimmune connective tissue disease with the highest morbidity and mortality, through the combination of inflammation, vasculopathy and fibrosis leading to severe internal organ involvement. Currently, there are no approved diseasemodifying therapies, and treatment is based on organ-specific treatment and broad immunosuppression, with disappointing long-term results in most cases. Recent research has helped to improve knowledge of the pathogenesis of systemic sclerosis and to optimize treatment based on specific physiopathological targets, and a new era of biological agents in systemic sclerosis has now begun. Promising results are emerging from targeting specific cytokine signalling, especially IL-6, and cellular subpopulations such as B cells, with anti-CD20 therapy, and T-cells, with inhibition of T-cell co-stimulation. Other approaches under evaluation are based on the modulation of profibrotic pathways by anti-TGF-β agents. In this chapter, we discuss the available evidence to support the use of each biological agent in systemic sclerosis based on data from basic and translational research and on results from clinical studies.

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“…The effect of abatacept on T cell activation occurs via the removal of pro-inflammatory, costimulatory signals32 on antigen presenting cells39. Yet it can additionally be dependent on the production of anti-inflammatory signals, actively inhibiting the pathogenic response3040.…”

Section: Resultsmentioning

confidence: 99%

“…Abatacept is known to inhibit T cell activation and proliferation14 by blocking costimulatory ligands CD80 and CD86 on antigen presenting cells (dendritic cells, B cells and macrophages)39565758. Despite early contrasting data, abatacept has been shown not to act via induction of signals in dendritic cells5960.…”

Section: Discussionmentioning

confidence: 99%

“…Despite early contrasting data, abatacept has been shown not to act via induction of signals in dendritic cells5960. Yet, as it interacts with macrophages and B cells, it is not surprising that it can directly inhibit monocyte/macrophage activation and function3361 and B-cell function34395758. The functions of macrophages and B cells affected by abatacept are related to T cell-dependent responses333439, possibly as these functions involve CD80/CD86.…”

Section: Discussionmentioning

confidence: 99%

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T cell costimulation blockade blunts pressure overload-induced heart failure

et al. 2017

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Heart failure (HF) is a leading cause of mortality. Inflammation is implicated in HF, yet clinical trials targeting pro-inflammatory cytokines in HF were unsuccessful, possibly due to redundant functions of individual cytokines. Searching for better cardiac inflammation targets, here we link T cells with HF development in a mouse model of pathological cardiac hypertrophy and in human HF patients. T cell costimulation blockade, through FDA-approved rheumatoid arthritis drug abatacept, leads to highly significant delay in progression and decreased severity of cardiac dysfunction in the mouse HF model. The therapeutic effect occurs via inhibition of activation and cardiac infiltration of T cells and macrophages, leading to reduced cardiomyocyte death. Abatacept treatment also induces production of anti-inflammatory cytokine interleukin-10 (IL-10). IL-10-deficient mice are refractive to treatment, while protection could be rescued by transfer of IL-10-sufficient B cells. These results suggest that T cell costimulation blockade might be therapeutically exploited to treat HF.

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Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis

Cited by 61 publications

References 39 publications

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

PI3Kβ Plays a Key Role in Apolipoprotein A-I-Induced Endothelial Cell Proliferation Through Activation of the Ecto-F1-ATPase/P2Y1 Receptors

Biological Therapy in Systemic Sclerosis

T cell costimulation blockade blunts pressure overload-induced heart failure

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