Date: Monday, October 22, 2018
Session Type: ACR Poster Session B
Session Time: 9:00AM-11:00AM
Background/Purpose: A previous report showed that abatacept (IgG-CTLA-4) prevented and induced regression of inflammation-driven dermal fibrosis in two different mouse models of systemic sclerosis (SSc) (1). 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 involvements of 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: Treatment with abatacept was well tolerated in all mouse models. In the cGvHD model, treatment of allogeneically transplanted mice with abatacept led to a significant reduction of alanine aminotransferase (24%, P=0.014) and aspartate aminotransferase levels (61%, P<0.001). Pathological analysis of colon revealed decreased inflammatory infiltrates and destruction of crypts in allogeneically mice receiving abatacept. When assessed by chest micro-CT imaging, Fra-2 transgenic mice treated with abatacept displayed a significant 12% decrease in lung density (10 mg/ml, P=0.037) as well as a marked increase in functional residual capacity as compared to IgG1-treated mice (16% for 1 mg/ml, P=0.001 and 14% for 10 mg/ml, P=0.005). Consistent with these results, abatacept 10mg/L decreased histological fibrosis score (Ashcroft score) as well as hydroxyproline content by 79% (P=0.009) and 31% (P=0.044) respectively, as compared to IgG1-treated mice. Treatment with abatacept 10mg/mL markedly reduced protein levels in the lesional lungs of Fra-2 transgenic mice of the fibrogenic markers MCP1 by 79% (P=0.043) and osteopontin by 87% (P=0.039). Levels of TGF-b were also reduced with abatacept (61% for 1mg/mL, P=0.037 and 69% for 10mg/mL, P=0.013). Further, abatacept dramatically decreased M1 and M2 macrophages infiltration as well as T-cell proliferation in the lesional lungs of Fra-2 mice. Upon treatment with abatacept a substantial reduction of right ventricular systolic pressure (28.1±1.5 mmHg vs. 36.0±5.1 mmHg, P=0.037 for 10mg/mL) and right ventricular hypertrophy (0.29±0.01 vs. 0.33±0.010, P=0.037 and 29±0.01% vs. 0.33±0.01% for 10mg/mL, P=0.037) was observed compared to IgG1-treated mice. Consistent with these findings, abatacept 10mg/mL was associated with significant decrease in percent medial wall thickness and numbers of muscularized distal pulmonary arteries.
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.
References: (1) Ponsoye M et al. Ann Rheum Dis. 2016 Dec;75(12):2142–9
To cite this abstract in AMA style:Boleto G, Guignabert C, Pezet S, Cauvet A, Sadoine J, Tu L, Nicco C, Gobeaux C, Batteux F, Allanore Y, Avouac J. Abatacept Is Effective in Experimental Digestive and Lung Tissue Fibrosis [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/abatacept-is-effective-in-experimental-digestive-and-lung-tissue-fibrosis/. Accessed August 3, 2020.
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