Background/Purpose: 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. 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. To assess whether abatacept might prevent the development of dermal fibrosis, mice received in parallel subcutaneous injections of bleomycin 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, 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. Tsk-1 mice received i.p injections of 100 mg of abatacept or control IgG1 every other day for 5 weeks. Infiltrating T cells, B cells and monocytes were quantified in lesional skin by immunohistochemistry for CD3, CD22 and CD68. Inflammatory cytokines were measured in lesional skin by flow cytometry.

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 this model, treatment with abatacept led to decreased T cell, B cell and monocyte infiltration in the lesional skin. Upon bleomycin injections, skin IL-6 and IL-10 levels were significantly reduced upon abatacept treatment.

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.

Conclusion: Using complementary mouse models of SSc, we demonstrate that abatacept can prevent and induce the regression of inflammation-driven experimental dermal fibrosis. Antifibrotic effects of abatacept are mediated in the bleomycin mouse model by the reduction of T cell, B cell and monocyte infiltration into lesional skin, and by the decreased of IL-6 and IL-10 skin levels. 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.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/treatment-with-abatacept-prevents-experimental-dermal-fibrosis-and-induces-regression-of-established-inflammation-driven-fibrosis/