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.
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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. / Avouac, Jérôme; Elhai, Muriel; Tomcik, Michal; Ruiz, Barbara; Friese, Manuel A.; Piedavent, Melanie; Colonna, Marco; Bernhardt, Gunter; Kahan, André; Chiocchia, Gilles; Distler, Jörg H W; Allanore, Yannick.
in: ANN RHEUM DIS, Jahrgang 72(6), 2012, S. 1089-1098.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - 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.
AU - Avouac, Jérôme
AU - Elhai, Muriel
AU - Tomcik, Michal
AU - Ruiz, Barbara
AU - Friese, Manuel A.
AU - Piedavent, Melanie
AU - Colonna, Marco
AU - Bernhardt, Gunter
AU - Kahan, André
AU - Chiocchia, Gilles
AU - Distler, Jörg H W
AU - Allanore, Yannick
PY - 2012
Y1 - 2012
N2 - 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-? 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.
AB - 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-? 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.
M3 - SCORING: Journal article
VL - 72(6)
SP - 1089
EP - 1098
JO - ANN RHEUM DIS
JF - ANN RHEUM DIS
SN - 0003-4967
ER -