• English
  • Deutsch
  • Log In
    Password Login
    Research Outputs
    Fundings & Projects
    Researchers
    Institutes
    Statistics
Repository logo
Fraunhofer-Gesellschaft
  1. Home
  2. Fraunhofer-Gesellschaft
  3. Artikel
  4. Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis
 
  • Details
  • Full
Options
2020
Journal Article
Title

Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis

Abstract
Objective Systemic sclerosis (SSc) is characterized by fibrosis, vascular disease, and inflammation. Adenosine signaling plays a central role in fibroblast activation. We undertook this study to evaluate the therapeutic effects of adenosine depletion with PEGylated adenosine deaminase (PEG‐ADA) in preclinical models of SSc. Methods The effects of PEG‐ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra‐2 mice and in a B10.D2RTBALB/c (H‐2d) model of sclerodermatous chronic graft‐versus‐host disease (GVHD). The effects of PEG‐ADA were confirmed in vitro in a human full‐thickness skin model. Results PEG‐ADA effectively inhibited myofibroblast differentiation and reduced pulmonary fibrosis by 34.3% (with decreased collagen expression) (P = 0.0079; n = 6), dermal fibrosis by 51.8% (P = 0.0006; n = 6), and intestinal fibrosis by 17.7% (P = 0.0228; n = 6) in Fra‐2 mice. Antifibrotic effects of PEG‐ADA were also demonstrated in sclerodermatous chronic GVHD (reduced by 38.4%) (P = 0.0063; n = 8), and in a human full‐thickness skin model. PEG‐ADA treatment decreased inflammation and corrected the M2/Th2/group 2 innate lymphoid cell 2 bias. Moreover, PEG‐ADA inhibited proliferation of pulmonary vascular smooth muscle cells (reduced by 40.5%) (P < 0.0001; n = 6), and prevented thickening of the vessel walls (reduced by 39.6%) (P = 0.0028; n = 6) and occlusions of pulmonary arteries (reduced by 63.9%) (P = 0.0147; n = 6). Treatment with PEG‐ADA inhibited apoptosis of microvascular endothelial cells (reduced by 65.4%) (P = 0.0001; n = 6) and blunted the capillary rarefication (reduced by 32.5%) (P = 0.0199; n = 6). RNA sequencing demonstrated that treatment with PEG‐ADA normalized multiple pathways related to fibrosis, vasculopathy, and inflammation in Fra‐2 mice. Conclusion Treatment with PEG‐ADA ameliorates the 3 cardinal features of SSc in pharmacologically relevant and well‐tolerated doses. These findings may have direct translational implications, as PEG‐ADA has already been approved by the Food and Drug Administration for the treatment of patients with ADA‐deficient severe combined immunodeficiency disease.
Author(s)
Zhang, Yun
Zhu, Honglin
Layritz, Florian
Luo, Hui
Wohlfahrt, Thomas
Chen, Chih-Wei
Soare, Alina
Bergmann, Christina
Ramming, Andreas
Groeber-Becker, Florian  
Reuter, Christian
Fornasini, GianFranco
Soukhareva, Nadejda
Schreiber, Brian
Ramamurthy, Santosh
Amann, Kerstin
Schett, Georg
Distler, Jörg H.W
Journal
Arthritis & rheumatology  
DOI
10.1002/art.41259
Language
English
Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB  
Fraunhofer-Institut für Silicatforschung ISC  
Keyword(s)
  • adenosine deaminase

  • collagen

  • transcription factor Fra 2

  • systemic sclerosis

  • skin fibrosis

  • Cookie settings
  • Imprint
  • Privacy policy
  • Api
  • Contact
© 2024