Combination therapy blocking TNF superfamily members 14 and 15 reverses pulmonary fibrosis

博莱霉素 纤维化 医学 肺纤维化 肿瘤坏死因子α 炎症 癌症研究 特发性肺纤维化 免疫学 内科学 化疗
作者
Hope Steele,Ashley Willicut,Garrison Dell,Andrew Ghastine,Xinh-Xinh Nguyen,Paul Lembicz,Hailey Doerflein,Therese Suchoski,Ellen Emi Kato,Carol Feghali‐Bostwick,Michael Croft,Rana Herro
出处
期刊:Journal of Immunology [American Association of Immunologists]
卷期号:214 (4): 808-817 被引量:3
标识
DOI:10.1093/jimmun/vkaf002
摘要

Abstract Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis and tissue remodeling in the clinic. Thus, there is an unmet need to develop novel antifibrotic drugs capable of reversing disease. Our lab has identified two novel mediators of pulmonary fibrosis belonging to the tumor necrosis factor superfamily (TNFSF), LIGHT (TNFSF14) and TL1A (TNFSF15). Aside from their inflammatory roles, LIGHT and TL1A can directly activate structural cells involved in fibrosis, which express their receptors. Here, we show that LIGHT and TL1A receptors are both significantly elevated in patient pulmonary fibrosis biopsies as compared with healthy control lungs. Using gain-of-function studies, we found that LIGHT and TL1A can drive airway remodeling independently of one another. Furthermore, these TNFSF members synergize to maximize airway inflammation and fibrosis. We show that the combinatorial blockade of LIGHT and TL1A limits transforming growth factor β–driven profibrotic effects on fibroblasts in vitro. Moreover, LIGHT and TL1A stimulation of human epithelial cells and fibroblasts reveal distinct fibrotic signatures, including additive and synergistic profibrotic activities, in addition to some redundant profibrotic functions. Importantly, using antagonistic reagents neutralizing both LIGHT and TL1A signaling concomitantly post–disease onset in a bleomycin mouse model of pulmonary fibrosis, we observe a significant decrease in collagen deposition and smooth muscle accumulation as opposed to respective monotherapies blocking each molecule in isolation. This work highlights a therapeutic need to concomitantly target LIGHT and TL1A for treatment of pulmonary fibrosis disorders in humans.
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