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FRI0438 Treatment with Abatacept Prevents Experimental Dermal FIBrosis and Induces Regression of Established Fibrosis in a Preclinical Model of Systemic Sclerosis
  1. M. Ponsoye1,
  2. C. Frantz1,
  3. N. Ruzehaji1,
  4. M. Elhai1,
  5. B. Ruiz1,
  6. A. Cauvet1,
  7. Y. Allanore2,
  8. J. Avouac2
  1. 1INSERM U1016, Cochin Institute
  2. 2Rheumatology A Department, Paris Descartes University, Cochin Hospital, Paris, France

Abstract

Background Early stages of systemic sclerosis (SSc) are characterized by inflammatory skin infiltrates mainly composed of activated T cells. Cytotoxic T-lymphocyte associated molecule-4 (CTLA-4) is a key regulator of T cell activation and preliminary data have suggested that it might contribute to SSc.

Objectives Our aim was to investigate the efficacy of the CTLA-4-Ig abatacept, an inhibitor of T cell activation, in reducing skin fibrosis in complementary mouse models of SSc.

Methods We first evaluated the antifibrotic properties of abatacept in the mouse model of bleomycin-induced dermal fibrosis, reflecting early and inflammatory stages of SSc. To assess whether abatacept might prevent the development of dermal fibrosis, six-week-old C57BL/6 mice received in parallel subcutaneous injections bleomycin (0.5 mg/ml) and intraperitoneal (i.p) injections of abatacept or purified human IgG1 at a dose of 100 mg every other day for three weeks. To assess whether abatacept might induce the regression of established dermal fibrosis, six-week-old C57BL/6 mice were challenged with bleomycin for 6 weeks and received i.p injections of 100 mg of abatacept or control IgG1 every other day during the last 3 weeks. Then, we investigated abatacept in the tight skin (Tsk-1) mice, an inflammation-independent mouse model of skin fibrosis. To this end, five-week-old Tsk-1 mice received i.p injections of 100 mg of abatacept or control IgG1 every other day for 5 weeks. Infiltrating leukocytes and T cells were quantified in lesional skin by immunohistochemistry.

Results Treatment with abatacept prevented the induction of bleomycin-induced dermal fibrosis: dermal thickness was significantly reduced by 48±5% in mice treated with abatacept compared to mice receiving the control IgG1 (p=0.03). Consistent with decreased dermal thickness, hydroxyproline content and myofibroblast counts were reduced upon treatment with abatacept by 63±4% (p=0.02) and 41±6% (p=0.04) respectively, compared to mice receiving the control antibody. In addition, treatment with abatacept led to decreased leukocyte and T cell infiltrates in the lesional skin of mice challenged with bleomycin. Abatacept also induced the regression of established bleomycin-induced dermal fibrosis: dermal thickness, hydroxyproline content and myofibroblast counts were reduced by 15±2% (p<0.01), 16±3% (p<0.01) and 33±5% (p=0.01) respectively, compared to mice receiving control antibody. Abatacept demonstrated no efficacy in Tsk-1 mice.

Conclusions Using complementary mouse models of SSc, we demonstrate that abatacept can prevent and induce the regression of inflammation-driven experimental dermal fibrosis. Translation to human disease is now required, and targeting early and inflammatory stages of SSc sounds the most appropriate. This strategy is currently under investigation in a phase-3 clinical trial assessing the efficacy of abatacept to improve skin involvement in patients with early diffuse SSc.

Disclosure of Interest None declared

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