title: Treatment with abatacept prevents experimental dermal fibrosis and induces regression of established inflammation-driven fibrosis.
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.
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Matthieu
authors.initials: M
authors.lastname: Ponsoye
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Camelia
authors.initials: C
authors.lastname: Frantz
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Nadira
authors.initials: N
authors.lastname: Ruzehaji
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Nicco
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Muriel
authors.initials: M
authors.lastname: Elhai
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Cauvet
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Pezet
authors.affiliation: Service de Pharmacie Clinique, GH Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France.
authors.forename: Marie Laure
authors.initials: ML
authors.lastname: Brandely
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.|Laboratoire d'Immunologie biologique, Hôpital Cochin, AP-HP, Paris, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Batteux
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France.
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
authors.affiliation: Université Paris Descartes, Sorbonne Paris Cité, INSERM U1016 and CNRS UMR8104, Institut Cochin, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, Service de Rhumatologie A, Hôpital Cochin, Paris, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Avouac
mesh_terms: D000069594:Abatacept / Q000494:pharmacology*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D001761:Bleomycin; D004195:Disease Models, Animal; D005355:Fibrosis; D006086:Graft vs Host Disease / Q000188:drug therapy; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D012595:Scleroderma, Systemic / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D012871:Skin Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D013601:T-Lymphocytes / Q000187:drug effects*
chemical_list: C556062:IL10 protein, mouse; D015850:Interleukin-6; C577686:interleukin-6, mouse; D001761:Bleomycin; D016753:Interleukin-10; D000069594:Abatacept
keywords: Inflammation; Systemic Sclerosis; T Cells