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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
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-1mice. 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. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
Entities:
Keywords:
Inflammation; Systemic Sclerosis; T Cells
Authors: Dinesh Khanna; Cathie Spino; Sindhu Johnson; Lorinda Chung; Michael L Whitfield; Christopher P Denton; Veronica Berrocal; Jennifer Franks; Bhavan Mehta; Jerry Molitor; Virginia D Steen; Robert Lafyatis; Robert W Simms; Anna Gill; Suzanne Kafaja; Tracy M Frech; Vivien Hsu; Robyn T Domsic; Janet E Pope; Jessica K Gordon; Maureen D Mayes; Elena Schiopu; Amber Young; Nora Sandorfi; Jane Park; Faye N Hant; Elana J Bernstein; Soumya Chatterjee; Flavia V Castelino; Ali Ajam; Yue Wang; Tammara Wood; Yannick Allanore; Marco Matucci-Cerinic; Oliver Distler; Ora Singer; Erica Bush; David A Fox; Daniel E Furst Journal: Arthritis Rheumatol Date: 2019-12-10 Impact factor: 10.995
Authors: Lorinda Chung; Cathie Spino; Richard McLain; Sindhu R Johnson; Christopher P Denton; Jerry A Molitor; Virginia D Steen; Robert Lafyatis; Robert W Simms; Suzanne Kafaja; Tracy M Frech; Vivien Hsu; Robyn T Domsic; Janet E Pope; Jessica K Gordon; Maureen D Mayes; Nora Sandorfi; Faye N Hant; Elana J Bernstein; Soumya Chatterjee; Flavia V Castelino; Ali Ajam; Yannick Allanore; Marco Matucci-Cerinic; Michael L Whitfield; Oliver Distler; Ora Singer; Amber Young; Vivek Nagaraja; David A Fox; Daniel E Furst; Dinesh Khanna Journal: Lancet Rheumatol Date: 2020-10-19