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Critical role of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of inflammation-driven dermal fibrosis in a mouse model of systemic sclerosis
  1. Jérôme Avouac1,2,
  2. Muriel Elhai2,
  3. Michal Tomcik3,4,
  4. Barbara Ruiz2,
  5. Manuel Friese5,
  6. Melanie Piedavent5,
  7. Marco Colonna6,
  8. Gunter Bernhardt7,
  9. André Kahan1,
  10. Gilles Chiocchia2,
  11. Jörg H W Distler3,
  12. Yannick Allanore1,2
  1. 1Rheumatology A Department, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, Paris, France
  2. 2Cochin Institute, Paris Descartes University, INSERM U1016 and CNRS UMR8104, Paris, France
  3. 3Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany
  4. 4Department of Rheumatology of the First Faculty of Medicine, Institute of Rheumatology and Connective Tissue Research Laboratory, Charles University in Prague, Czech Republic
  5. 5Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany
  6. 6Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA
  7. 7Institute of Immunology, Hannover Medical School, Hannover, Germany
  1. Correspondence to Dr Jérôme Avouac, Rheumatology A Department, Paris Descartes University, Cochin Hospital, 27 rue du Faubourg Saint Jacques, Paris 75014, France; jerome.avouac{at}


Objective To investigate the contribution of the adhesion receptor DNAX accessory molecule-1 (DNAM-1) in the development of dermal fibrosis on gene inactivation and targeted molecular strategies.

Methods Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1−/−) and wild-type controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leucocytes, T cells, B cells and monocytes were quantified and inflammatory cytokines were measured in lesional skin of dnam1−/− and dnam1+/+ mice. The anti-fibrotic potential of a DNAM-1 neutralising monoclonal antibody (mAb) was evaluated in the mouse model of bleomycin-induced dermal fibrosis.

Results Overexpression of DNAM-1 was detected in the skin of patients with SSc (systemic sclerosis). Dnam1−/− mice were protected from bleomycin-induced dermal fibrosis with reduction of dermal thickening (75±5%, p=0.03), hydroxyproline content (46±8%, p=0.04) and myofibroblast counts (39±5%, p=0.01). Moreover, the number of T cells was significantly decreased in lesional skin of dnam1−/− mice (69±15%, p=0.0007). Dnam1−/− mice also displayed decreased levels of TNF-α and IL-6 in lesional skin. Consistent with the gene inactivation strategy, treatment of mice with DNAM-1 neutralising mAb prevented dermal fibrosis induced by bleomycin with reduction of dermal thickness (64±6%, p=0.002), hydroxyproline content (61±8%, p=0.004) and myofibroblast counts (83±12%, p=0.002).

Conclusions An inactivation gene strategy showed that DNAM-1 exerts profibrotic effects by controlling T cell activation and cytokine release. A molecular targeted strategy confirmed that DNAM-1 neutralising mAb has potent antifibrotic properties, supporting the hypothesis that inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other related fibrotic diseases.

  • Systemic Sclerosis
  • T Cells
  • Inflammation

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