ACR Meeting Abstracts

ACR Meeting Abstracts

Abstract Number: 1510

Critical Role of the Adhesion Receptor Dnax Accessory Molecule-1 (DNAM-1) in the Development of Inflammation-Driven Dermal Fibrosis in Mouse Model of Systemic Sclerosis

Jerome Avouac1, Muriel Elhai2, Michal Tomcik3, Manuel Friese4, Marco Colonna5, Günter Bernhardt6, Andre Kahan7, Gilles Chiocchia8, Joerg HW Distler9 and Yannick Allanore10, 1Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France, 2Paris Descartes University, INSERM U1016, Institut Cochin, Sorbonne Paris Cité, Paris, France, 3Institute of Rheumatology, Department of Rheumatology, 1st Faculty of Medicine, Charles University, Prague 2, Czech Republic, 4Zentrum für Molekulare Neurobiologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany, 5Washington University, Department of Immunology, St. Louis, MO, 6Institute of Immunology, Hannover Medical School, Hannover, Germany, 7Rheumatology A Department, Cochin Hospital, APHP, Paris Descartes University, Paris, France, 8Immunology and Hematology Department, Institut Cochin - INSERM U1016 - CNRS (UMR 8104), Paris, France, 9Department of Internal Medicine III and Institute for Clinical Immunology, University of Erlangen-Nuremberg, Erlangen, Germany, 10Rheumatology, Paris Descartes University, Rheumatology A department, Cochin Hospital, Paris, France

Meeting: 2012 ACR/ARHP Annual Meeting

Keywords:

Session Information

Title: Systemic Sclerosis, Fibrosing Syndromes and Raynaud’s – Pathogenesis, Animal Models and Genetics

Session Type: Abstract Submissions (ACR)

Background/Purpose: DNAX accessory molecule 1 (DNAM-1) is an adhesion factor involved in the adhesion and co-stimulation of T cells. DNAM-1 has been recently identified as a genetic susceptibility factor to systemic sclerosis (SSc) and also to other autoimmune diseases. Our aim was to investigate the contribution of DNAM-1 in the development of dermal fibrosis upon gene inactivation and targeted molecular strategies.

Methods: Human skin expression of DNAM-1 was determined by immunohistochemistry. Mice deficient for DNAM-1 (dnam1-/-) and wildtype controls (dnam1+/+) were injected with bleomycin or NaCl. Infiltrating leukocytes, T cells, B cells and monocytes were quantified respectively on hematoxylin and eosin stained sections and by immunohistochemistry for CD3, CD22 and CD68. Inflammatory cytokines were measured in lesional skin of dnam1-/- and dnam1+/+mice by flow cytometry. The anti-fibrotic potential of a DNAM-1 neutralizing monoclonal antibody (mAb) was also evaluated in the mouse model of bleomycin-induced dermal fibrosis.

Results: Overexpression of DNAM-1 was detected in the lesional skin of SSc patients, especially in perivascular inflammatory cells. Dnam1-/- mice were protected from bleomycin-induced dermal fibrosis with reduced dermal thickening (75±5% reduction, p=0.02), hydroxyproline content (46±8% decrease, p=0.02) and myofibroblast counts (39±5% reduction, p=0.04). The numbers infiltrating T cells were decreased in lesional skin of dnam1-/- mice by 69±15% (p=0.009). The number of B cells and monocytes was not significantly different in dnam1-/- and dnam1+/+ mice upon bleomycin challenge. Moreover, dnam1-/-mice displayed in lesional skin decreased levels of inflammatory cytokines, such as IL-6 (59±12%, p=0.001 decrease), and TNFα (60±15%, p=0.03). Treatment with anti-DNAM-1 mAb significantly reduced dermal thickening by 64±6% (p=0.01), hydroxyproline content by 61±8% (p=0.001), and myofibroblast counts by 83±12% (P=0.03). These results were similar to those observed in DNAM-1 deficient mice.

Conclusion: We demonstrate with two complementary approaches that inhibition of DNAM-1 significantly ameliorates dermal inflammation-driven fibrosis. DNAM-1 displays profibrotic effects by promoting the infiltration of T cells, into lesional skin and by stimulating the release of inflammatory cytokines. In addition, molecular targeting strategy using a DNAM-1 neutralizing mAb confirmed potent antifibrotic properties of DNAM-1 inhibition. Our findings might have direct translational implications and inhibition of DNAM-1 might be a promising new approach for the treatment of SSc and potentially other fibrotic diseases.

Disclosure:

J. Avouac,
None;

M. Elhai,
None;

M. Tomcik,
None;

M. Friese,
None;

M. Colonna,
None;

G. Bernhardt,
None;

A. Kahan,
None;

G. Chiocchia,
None;

J. H. Distler,
None;

Y. Allanore,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/critical-role-of-the-adhesion-receptor-dnax-accessory-molecule-1-dnam-1-in-the-development-of-inflammation-driven-dermal-fibrosis-in-mouse-model-of-systemic-sclerosis/