title: 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.
abstract: 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.
authors.affiliation: Rheumatology A Department, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, Paris, France. jerome.avouac@cch.aphp.fr
authors.forename: Jérôme
authors.initials: J
authors.lastname: Avouac
authors.forename: Muriel
authors.initials: M
authors.lastname: Elhai
authors.forename: Michal
authors.initials: M
authors.lastname: Tomcik
authors.forename: Barbara
authors.initials: B
authors.lastname: Ruiz
authors.forename: Manuel
authors.initials: M
authors.lastname: Friese
authors.forename: Melanie
authors.initials: M
authors.lastname: Piedavent
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.forename: Gunter
authors.initials: G
authors.lastname: Bernhardt
authors.forename: André
authors.initials: A
authors.lastname: Kahan
authors.forename: Gilles
authors.initials: G
authors.lastname: Chiocchia
authors.forename: Jörg H W
authors.initials: JH
authors.lastname: Distler
authors.forename: Yannick
authors.initials: Y
authors.lastname: Allanore
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000502:physiology*; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D012595:Scleroderma, Systemic / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D012867:Skin / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D000098862:T Lineage-Specific Activation Antigen 1
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D000098862:T Lineage-Specific Activation Antigen 1; D016207:Cytokines