University of Erlangen-Nuremberg, Erlangen, Germany.
University of Erlangen-Nuremberg, Erlangen, Germany, and Xiangya Hospital and Central South University, Changsha, China.
Arthritis Rheumatol. 2020 Aug;72(8):1385-1395. doi: 10.1002/art.41259. Epub 2020 Jun 25.
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.
The 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-2 ) 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.
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.
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.
系统性硬化症（SSc）的特征是纤维化、血管疾病和炎症。腺苷信号在成纤维细胞激活中起着核心作用。我们进行这项研究是为了评估聚乙二醇化腺苷脱氨酶（PEG-ADA）在 SSc 的临床前模型中的腺苷耗竭的治疗效果。
在 Fra-2 小鼠和 B10.D2→BALB/c（H-2）硬皮病慢性移植物抗宿主病（GVHD）模型中，分析了 PEG-ADA 对炎症、血管重塑和组织纤维化的影响。在人全厚皮肤模型中，通过体外实验证实了 PEG-ADA 的作用。
PEG-ADA 有效抑制了肌成纤维细胞的分化，并通过 34.3%（胶原表达减少）（P=0.0079；n=6）、51.8%（P=0.0006；n=6）和 17.7%（P=0.0228；n=6）减少了 Fra-2 小鼠的肺纤维化、皮肤纤维化和肠道纤维化。PEG-ADA 在硬皮病慢性 GVHD（减少 38.4%）（P=0.0063；n=8）和人全厚皮肤模型中也显示出抗纤维化作用。PEG-ADA 治疗减少了炎症，并纠正了 M2/Th2/2 型固有淋巴细胞 2 的偏向。此外，PEG-ADA 抑制了肺血管平滑肌细胞的增殖（减少 40.5%）（P＜0.0001；n=6），并防止了血管壁的增厚（减少 39.6%）（P=0.0028；n=6）和肺动脉的闭塞（减少 63.9%）（P=0.0147；n=6）。PEG-ADA 治疗抑制了微血管内皮细胞的凋亡（减少 65.4%）（P=0.0001；n=6），并减弱了毛细血管稀疏（减少 32.5%）（P=0.0199；n=6）。RNA 测序表明，PEG-ADA 治疗使 Fra-2 小鼠中与纤维化、血管病变和炎症相关的多个途径正常化。
PEG-ADA 以具有药理意义且耐受良好的剂量改善 SSc 的 3 个主要特征。这些发现可能具有直接的转化意义，因为 PEG-ADA 已被美国食品和药物管理局批准用于治疗 ADA 缺乏性严重联合免疫缺陷病患者。
