Article Text
Abstract
Objectives We aimed to assess the expression of the CCL24 chemokine in systemic sclerosis (SSc) and to evaluate the possible pathogenic implications of the CCL24/CCR3 axis using both in vitro and in vivo models. We further investigated the efficacy of an anti-CCL24 monoclonal antibody (mAb), CM-101, in inhibiting cell activation as well as dermal and pulmonary inflammation and fibrosis in experimental animal models.
Methods We used ELISA and fluorescence immunohistochemistry to determine CCL24 levels in serum and CCL24/CCR3 expression in skin biopsies of SSc patients. Skin fibroblasts and endothelial cells treated with CCL24 or SSc serum with or without CM-101 were used to follow cell activation and differentiation. Prevention and treatment in vivo bleomycin (BLM)-induced models were used to evaluate experimental dermal and pulmonary fibrosis progression following treatment with the CM-101 mAb.
Results CCL24 circulating levels were significantly elevated in SSc patients. CCL24/CCR3 expression was strongly increased in SSc skin. Blockade of CCL24 with CM-101 significantly reduced the activation of dermal fibroblasts and their transition to myofibroblasts induced by SSc serum. CM-101 was also able to significantly inhibit endothelial cell activation induced by CCL24. In BLM-induced experimental animal models, CM-101 profoundly inhibited both dermal and pulmonary fibrosis and inflammation.
Conclusions CCL24 plays an important role in pathological processes of skin and lung inflammation and fibrosis. Inhibition of CCL24 by CM-101 mAb can be potentially beneficial for therapeutic use in SSc patients.
- systemic sclerosis
- pulmonary fibrosis
- inflammation
- chemokines
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Footnotes
Handling editor Josef S Smolen
Contributors AM: Substantial contributions to the conception and design of the work. Drafting the work and final approval of the version to be published. MSS and NB: Analysis and interpretation of data for the work; drafting the work and revising it for publication. AK and VE: Data acquisition. MM: Immunostaining data acquisition, analysis and interpretation; drafting the work and revising it for publication. YL and JG: Revision for publication. MM-C: Revising the work critically for publication. All the authors were involved in the development, review and approval of the manuscript.
Funding This research has received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests AM, MSS, AK, NB and VE: ChemomAb employees. JG: ChemomAb consultant. MM-C: ChemomAb consultant, BMS, MSD, Actelion, Sanofi and Biogen.
Ethics approval Serum samples from systemic sclerosis patients were taken following Helsinki ethics committee approval (Meir Medical Center, Kfar-Saba, Israel). Archival skin specimens were taken under protocols approved by the local institutional review board at the Azienda Ospedaliero-Universitaria Careggi (AOUC), Florence, Italy. Studies involving animal models were approved by the National Board of Animal Studies in the Ministry of Health by the Kaplan Medical Center.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data of SSc patients and control participants belong to the Meir Medical Center, Kfar-Saba, Israel, and are not publicly available.