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.

Jérôme Avouac, Muriel Elhai, Michal Tomcik, Barbara Ruiz, Manuel Friese, Melanie Piedavent, Marco Colonna, Gunter Bernhardt, André Kahan, Gilles Chiocchia, Jörg H W Distler, Yannick Allanore

Rheumatology A Department, Paris Descartes University, Sorbonne Paris Cité, Cochin Hospital, Paris, France. jerome.avouac@cch.aphp.fr

Annals of the rheumatic diseases 2013 Jun

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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. 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. 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). 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.

Citation

Jérôme Avouac, Muriel Elhai, Michal Tomcik, Barbara Ruiz, Manuel Friese, Melanie Piedavent, Marco Colonna, Gunter Bernhardt, André Kahan, Gilles Chiocchia, Jörg H W Distler, Yannick Allanore. 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. Annals of the rheumatic diseases. 2013 Jun;72(6):1089-98