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.
- Systemic Sclerosis
- T Cells
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Handling editor Tore K Kvien
Correction notice This article has been corrected since it was published Online First. The surname of the third author has been corrected.
Contributors Conception of the study: YA, JA, FB; data acquisition: MP, CF, NR, ME, BR, AC, SP, MPB, CN; data analysis and interpretation: MP, JA, YA, FB; draft and revision of the manuscript: MP, YA, JA; final approval of the manuscript: MP, CF, NR, CN, ME, BR, AC, SP, MPB, FB, YA, JA.
Funding Financial support and study drug were supplied by Bristol–Myers–Squibb, Co. Bristol–Myers–Squibb, Co. was not involved in the study design, data acquisition, data analysis or writing of the manuscript. Financial support was also supplied by the ‘Association des Sclérodermiques de France’.
Competing interests YA has/had consultancy relationship and/or has received research funding in relationship with the treatment of systemic sclerosis from Actelion, Bayer, Biogen Idec, Bristol–Myers–Squibb, Genentech/ Roche, Inventiva, Medac, Pfizer, Sanofi/Genzyme, Servier and UCB. JA has received research funding in relationship with the treatment of systemic sclerosis from Roche and Bristol–Myers–Squibb.
Provenance and peer review Not commissioned; externally peer reviewed.