Authors: Yun Zhang, Honglin Zhu, Florian Layritz, Hui Luo, Thomas Wohlfahrt, Chih‐Wei Chen, Alina Soare, Christina Bergmann, Andreas Ramming, Florian Groeber, Christian Reuter, GianFranco Fornasini, Nadejda Soukhareva, Brian Schreiber, Santosh Ramamurthy, Kerstin Amann, Georg Schett, Jörg H. W. Distler
Published: 2020-03-17
DOI: 10.1002/art.41259
Source: Full article
ObjectiveSystemic 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.MethodsThe effects of PEG‐ADA on inflammation, vascular remodeling, and tissue fibrosis were analyzed in Fra‐2 mice and in a B10.D2→BALB/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.ResultsPEG‐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.ConclusionTreatment 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.