OX40L blockade protects against inflammation-driven fibrosis.
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.
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France; Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France;
Muriel
M
Elhai
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France; Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France;
Jérôme
J
Avouac
Department of Rheumatology, Oslo University Hospital, 0873 Oslo, Norway;
Anna Maria
AM
Hoffmann-Vold
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Nadira
N
Ruzehaji
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Olivia
O
Amiar
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Barbara
B
Ruiz
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Hassina
H
Brahiti
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Matthieu
M
Ponsoye
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Maxime
M
Fréchet
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Anne
A
Burgevin
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Sonia
S
Pezet
Equipe d'Accueil (EA) 2496 Pathologie, Imagerie et Biothérapies Orofaciales, Faculty of Odontology, Paris Descartes University, Sorbonne Paris Cite, 92120 Montrouge, France; Plateforme d'Imagerie Du Vivant, Le Pôle de Recherche et d'Enseignement Supérieur Sorbonne Paris Cité, 92120 Montrouge, France;
Jérémy
J
Sadoine
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Thomas
T
Guilbert
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France;
Carole
C
Nicco
Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan;
Hisaya
H
Akiba
Research Unit Molecular Immune Regulation, Institute of Molecular Immunology, Helmholtz Zentrum München, DE-81377 Munich, Germany; Institute for Immunology, Ludwig-Maximilians-Universität München, DE-80336 Munich, Germany;
Vigo
V
Heissmeyer
Immune Mediated Diseases, Sanofi Genzyme, Framingham, MA 01701;
Arun
A
Subramaniam
Immune Mediated Diseases, Sanofi Genzyme, Framingham, MA 01701;
Robert
R
Resnick
Department of Rheumatology, Oslo University Hospital, 0873 Oslo, Norway;
Øyvind
Ø
Molberg
Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France;
André
A
Kahan
INSERM, U1173, Faculty of Health Sciences Simone Veil, Université Versailles-Saint-Quentin, 78180 Saint-Quentin-En-Yvelines, France.
Gilles
G
Chiocchia
INSERM, U1016 UMR8104, Cochin Institute, Paris Descartes University, Sorbonne Paris Cite, 75014 Paris, France; Rheumatology A Department, Cochin Hospital, Paris Descartes University, 75014 Paris, France; yannick.allanore@cch.aphp.fr.
Yannick
Y
Allanore
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001761:Bleomycin; D016022:Case-Control Studies; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D051921:Fos-Related Antigen-2 / Q000235:genetics; D006801:Humans; D006976:Hypertension, Pulmonary / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D053278:OX40 Ligand / Q000037:antagonists & inhibitors* / Q000097:blood*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000517:prevention & control*; D012595:Scleroderma, Systemic / Q000097:blood* / Q000188:drug therapy; D012867:Skin / Q000378:metabolism / Q000473:pathology*; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000911:Antibodies, Monoclonal; D015415:Biomarkers; D051921:Fos-Related Antigen-2; C497873:Fosl2 protein, mouse; D053278:OX40 Ligand; C089251:TNFSF4 protein, human; D018808:Transcription Factor AP-1; D001761:Bleomycin
OX40L; costimulation; fibrosis; systemic sclerosis; translational approach