OX40L blockade protects against inflammation-driven fibrosis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 113; no. 27; pp. E3901 - E3910
• Main Authors: Elhai, Muriel, Avouac, Jérôme, Hoffmann-Vold, Anna Maria, Ruzehaji, Nadira, Amiar, Olivia, Ruiz, Barbara, Brahiti, Hassina, Ponsoye, Matthieu, Fréchet, Maxime, Burgevin, Anne, Pezet, Sonia, Sadoine, Jérémy, Guilbert, Thomas, Nicco, Carole, Akiba, Hisaya, Heissmeyer, Vigo, Subramaniam, Arun, Resnick, Robert, Molberg, Øyvind, Kahan, André, Chiocchia, Gilles, Allanore, Yannick
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05-07-2016
• Series: From the Cover
• Subjects: Animals; Antibodies, Monoclonal - pharmacology; Antibodies, Monoclonal - therapeutic use; Biological Sciences; Biomarkers - blood; Bleomycin; Case-Control Studies; Cells, Cultured; Drug Evaluation, Preclinical; Fibrosis; Fos-Related Antigen-2 - genetics; Humans; Hypertension, Pulmonary - prevention & control; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Molecular Targeted Therapy; OX40 Ligand - antagonists & inhibitors; OX40 Ligand - blood; PNAS Plus; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - prevention & control; Scleroderma, Systemic - blood; Scleroderma, Systemic - drug therapy; Skin - metabolism; Skin - pathology; Transcription Factor AP-1 - metabolism; translational approach; fibrosis; systemic sclerosis; costimulation; OX40L
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1523512113

Treatment for fibrosis represents a critical unmet need, because fibrosis is the leading cause of death in industrialized countries, and there is no effective therapy to counteract the fibrotic process. The development of fibrosis relates to the interplay between vessel injury, immune cell activation, and fibroblast stimulation, which can occur in various tissues. Immunotherapies have provided a breakthrough in the treatment of immune diseases. The glycoprotein OX40–OX40 ligand (OX40L) axis offers the advantage of a targeted approach to costimulatory signals with limited impact on the whole immune response. Using systemic sclerosis (SSc) as a prototypic disease,we report compelling evidence that blockade of OX40L is a promising strategy for the treatment of inflammation-driven fibrosis. OX40L is overexpressed in the fibrotic skin and serum of patients with SSc, particularly in patients with diffuse cutaneous forms. Soluble OX40L was identified as a promising serum biomarker to predict the worsening of lung and skin fibrosis, highlighting the role of this pathway in fibrosis. In vivo, OX40L blockade prevents inflammation-driven skin, lung, and vessel fibrosis and induces the regression of established dermal fibrosis in different complementary mouse models. OX40L exerts potent profibrotic effects by promoting the infiltration of inflammatory cells into lesional tissues and therefore the release of proinflammatory mediators, thereafter leading to fibroblast activation.