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Ann Rheum Dis. 2016 Dec;75(12):2142-2149. doi: 10.1136/annrheumdis-2015-208213. Epub 2016 Feb 24.

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

Author information

1
Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
2
Service de Pharmacie Clinique, GH Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
3
Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France.
4
Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France.

Abstract

OBJECTIVE:

Activated T cells are the main component of the inflammatory skin infiltrates that characterise systemic sclerosis (SSc). Our aim was to investigate the efficacy of abatacept, which tempers T-cell activation, in reducing skin fibrosis in complementary mouse models of SSc.

METHODS:

The antifibrotic properties of abatacept were evaluated in the mouse models of bleomycin-induced dermal fibrosis and sclerodermatous chronic graft-versus-host disease, reflecting early and inflammatory stages of SSc. Thereafter, we studied the efficacy of abatacept in tight skin (Tsk-1) mice, an inflammation-independent mouse model of skin fibrosis.

RESULTS:

Abatacept efficiently prevented bleomycin-induced skin fibrosis and was also effective in the treatment of established fibrosis. In this model, abatacept decreased total and activated T-cell, B-cell and monocyte infiltration in the lesional skin. Abatacept did not protect CB17-SCID mice from the development of bleomycin-induced dermal fibrosis, which supports that T cells are necessary to drive the antifibrotic effects of abatacept. Upon bleomycin injections, skin interleukin (IL) 6 and IL-10 levels were significantly reduced upon abatacept treatment. Moreover, treatment with abatacept ameliorated fibrosis in the chronic graft-versus-host disease model, but demonstrated no efficacy in Tsk-1 mice. The tolerance of abatacept was excellent in the three mouse models.

CONCLUSIONS:

Using complementary models, we demonstrate that inhibition of T-cell activation by abatacept can prevent and induce the regression of inflammation-driven dermal fibrosis. Translation to human disease is now required, and targeting early and inflammatory stages of SSc sounds the most appropriate for positioning abatacept in SSc.

KEYWORDS:

Inflammation; Systemic Sclerosis; T Cells

PMID:
26912566
DOI:
10.1136/annrheumdis-2015-208213
[Indexed for MEDLINE]

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