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01.12.2018 | Research article | Ausgabe 1/2018 Open Access

Arthritis Research & Therapy 1/2018

T-cell costimulation blockade is effective in experimental digestive and lung tissue fibrosis

Zeitschrift:
Arthritis Research & Therapy > Ausgabe 1/2018
Autoren:
Gonçalo Boleto, Christophe Guignabert, Sonia Pezet, Anne Cauvet, Jérémy Sadoine, Ly Tu, Carole Nicco, Camille Gobeaux, Frédéric Batteux, Yannick Allanore, Jérôme Avouac
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1186/​s13075-018-1694-9) contains supplementary material, which is available to authorized users.

Abstract

Background

We aimed to investigate the efficacy of abatacept in preclinical mouse models of digestive involvement, pulmonary fibrosis, and related pulmonary hypertension (PH), mimicking internal organ involvement in systemic sclerosis (SSc).

Methods

Abatacept has been evaluated in the chronic graft-versus-host disease (cGvHD) mouse model (abatacept 1 mg/mL for 6 weeks), characterized by liver and intestinal fibrosis and in the Fra-2 mouse model (1 mg/mL or 10 mg/mL for 4 weeks), characterized by interstitial lung disease (ILD) and pulmonary vascular remodeling leading to PH.

Results

In the cGvHD model, abatacept significantly decreased liver transaminase levels and markedly improved colon inflammation. In the Fra-2 model, abatacept alleviated ILD, with a significant reduction in lung density on chest microcomputed tomography (CT), fibrosis histological score, and lung biochemical markers. Moreover, abatacept reversed PH in Fra-2 mice by improving vessel remodeling and related cardiac hemodynamic impairment. Abatacept significantly reduced fibrogenic marker levels, T-cell proliferation, and M1/M2 macrophage infiltration in lesional lungs of Fra-2 mice.

Conclusion

Abatacept improves digestive involvement, prevents lung fibrosis, and attenuates PH. These findings suggest that abatacept might be an appealing therapeutic approach beyond skin fibrosis for organ involvement in SSc.
Zusatzmaterial
Additional file 5: Abatacept alleviates inflammation-driven fibrosis by suppressing the immune response. Schematic cartoon of the mechanism of action of abatacept in systemic sclerosis (SSc) based on results presented in this study and previously published results in skin fibrosis [5]. In the early stages of SSc, T cells are activated through their TCR and receive costimulation via CD28 from CD80/CD86-expressing antigen-presenting cells. The full activation of T cells enhances the activation of dermal/lung fibroblasts through the action of proinflammatory and/or profibrotic cytokines (IL-6, IL-10). This also involves the proinflammatory action of macrophages. During abatacept treatment, the drug blocks CD80/CD86-mediated costimulation by macrophages and B cells, leading to inhibition of T-cell activation, proliferation, and/or infiltration. The effects on macrophages lead to lower maturation and infiltration. B-cell infiltration is also reduced. As a consequence of the effect on T cells, B cells, and macrophages, the progression of dermal, lung, and vessel fibrosis is blocked. (TIFF 1546 kb)
Literatur
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