Recombinant adenosine deaminase ameliorates inflammation, vascular disease and fibrosis in murine models of systemic sclerosis
Final Report Abstract
Systemic sclerosis (SSc), which associated with high mortality and severe morbidity, is a complex autoimmune disease involving not only skin but also any internal organs. SSc patients are suffering from the three cardinal characters of SSc: fibrosis, inflammation and vasculophathy. Several studies demonstrated the aberrant activation of adenosine pathway in SSc. To target all adenosine receptors for different organs and for all key characters of SSc in well-tolerant doses, we applied PEGylated adenosine deaminase (PEG-ADA) in two experimental mouse models of Fra2 transgenic mice and chronic graft-versus-host disease (cGvHD). In the preliminary work, we demonstrated that PEG-ADA treatment ameliorated dermal and pulmonary fibrosis in Fra2 mice. Moreover, PEG-ADA inhibited inflammation in Fra2 mice skin. In addition, PEG-ADA prevented the vasculopathy in the skin and lung of Fra2 mice. In the work program, firstly, we profiled the effects of Adenosine signalling by bulk RNA-Seq in Fra2 mice pulmonary tissue. PEG-ADA treatment inhibited ERK and SMAD signalling and normalized the genes related to fibrosis, vasculopathy, and inflammation in Fra2 mice lung. In addition, full-thickness-skin model with TGFβ-stimulated healthy fibroblasts and with SSc fibroblasts demonstrated reduced fibroblast activation with PEG-ADA treatment. Furthermore, both preventive and therapeutic treatment of PEG-ADA reduced cGvHD-induced dermal fibrosis. Similar as Fra2 mice, treatment with PEG-ADA ameliorates M2-driven inflammation in cGvHD-induced dermal fibrosis. Finally, PEG-ADA treatment ameliorated intestinal fibrosis in Fra2 mice. In the work programme about comparison of the antifibrotic efficacy of PEG-ADA with adenosine receptors antagonists in murine models of SSc, the planned animal models are still ongoing.
Publications
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PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis. Annals of the Rheumatic Diseases, 79(9), 1227-1233.
Zhang, Yun; Shen, Lichong; Zhu, Honglin; Dreissigacker, Katja; Distler, Diana; Zhou, Xiang; Györfi, Andrea Hermina; Bergmann, Christina; Meng, Xianyi; Dees, Clara; Trinh-Minh, Thuong; Ludolph, Ingo; Horch, Raymund; Ramming, Andreas; Schett, Georg & Distler, Jörg H. W.
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Recombinant Adenosine Deaminase Ameliorates Inflammation, Vascular Disease, and Fibrosis in Preclinical Models of Systemic Sclerosis. Arthritis & Rheumatology, 72(8), 1385-1395.
Zhang, Yun; Zhu, Honglin; Layritz, Florian; Luo, Hui; Wohlfahrt, Thomas; Chen, Chih‐Wei; Soare, Alina; Bergmann, Christina; Ramming, Andreas; Groeber, Florian; Reuter, Christian; Fornasini, GianFranco; Soukhareva, Nadejda; Schreiber, Brian; Ramamurthy, Santosh; Amann, Kerstin; Schett, Georg & Distler, Jörg H. W.
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TGF-β–induced epigenetic deregulation of SOCS3 facilitates STAT3 signaling to promote fibrosis. Journal of Clinical Investigation, 130(5), 2347-2363.
Dees, Clara; Pötter, Sebastian; Zhang, Yun; Bergmann, Christina; Zhou, Xiang; Luber, Markus; Wohlfahrt, Thomas; Karouzakis, Emmanuel; Ramming, Andreas; Gelse, Kolja; Yoshimura, Akihiko; Jaenisch, Rudolf; Distler, Oliver; Schett, Georg & Distler, Jörg H.W.
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Targeting of canonical WNT signaling ameliorates experimental sclerodermatous chronic graft-versus-host disease. Blood, 137(17), 2403–2416.
Zhang, Yun; Shen, Lichong; Dreißigacker, Katja; Zhu, Honglin; Trinh-Minh, Thuong; Meng, Xianyi; Tran-Manh, Cuong; Dees, Clara; Matei, Alexandru-Emil; Chen, Chih-Wei; Ditschkowski, Markus; Krauss, Stefan; Winkler, Julia; Wolff, Daniel; Ziemer, Mirjana; Beilhack, Andreas; Karrer, Sigrid; Herr, Wolfgang; Mackensen, Andreas ... & Distler, Jörg H. W.
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Noncanonical WNT5A controls the activation of latent TGF-β to drive fibroblast activation and tissue fibrosis. Journal of Clinical Investigation, 134(10).
Trinh-Minh, Thuong; Chen, Chih-Wei; Tran, Manh Cuong; Li, Yi-Nan; Zhu, Honglin; Zhou, Xiang; Chakraborty, Debomita; Zhang, Yun; Rauber, Simon; Dees, Clara; Lin, Neng-Yu; Kah, Delf; Gerum, Richard; Bergmann, Christina; Kreuter, Alexander; Reuter, Christiane; Groeber-Becker, Florian; Eckes, Beate; Distler, Oliver ... & Distler, Jörg H.W.
