Combination Therapy Blocking TNF Superfamily Members 14 and 15 Reverses Pulmonary Fibrosis

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Presentation Time: 09:00 AM - 09:15 AM
Abstract ID: 4830 - B

Presenting Author:
Hope Steele , Graduate Student at Cincinnati Children’s Hosp. Med. Ctr., Univ. of Cincinnati Col. of Med.

Abstract:

Currently, anti-inflammatory drugs fail to reduce pulmonary fibrosis in the clinic and there is an urgent unmet need to develop novel anti-fibrotic 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). Here, we show LIGHT and TL1A receptor are both significantly elevated in patient pulmonary fibrosis biopsies as compared to healthy control lungs. Using gain of function studies, we found that LIGHT and TL1A can drive airway remodeling independently of one another and that these TNFSF members synergize to maximize airway inflammation and fibrosis. We show that the combinatorial blockade of LIGHT and TL1A limits TGFb-driven profibrotic effects on fibroblasts in vitro. Moreover, LIGHT and TL1A stimulation of human epithelial cells and fibroblasts reveal distinct fibrotic and inflammatory signatures, including redundant, additive, and synergistic profibrotic activities. Importantly, using antagonistic reagents to neutralize both LIGHT and TL1A signaling in combination post-disease onset, we observe a significant decrease in collagen deposition and smooth muscle hypertrophy in a bleomycin model of pulmonary fibrosis as opposed to respective monotherapies. The implication of this work highlights a therapeutic need of concomitantly targeting LIGHT and TL1A to treat pulmonary fibrosis disorders in humans.