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PRECLINICAL STUDY

Atheroprotective Effect of CD31 Receptor Globulin Through Enrichment of Circulating Regulatory T-Cells

Emilie Groyer, MSc^_*, Antonino Nicoletti, PhD^_*, Hafid Ait-Oufella, MD, Jamila Khallou-Laschet, PhD^_*, Aditi Varthaman, MSc^_*, Anh-Thu Gaston, BSc^_*, Olivier Thaunat, MD^_*, Srini V. Kaveri, DVM, PhD^_*, Radek Blatny, MSc, Hannes Stockinger, PhD, Ziad Mallat, MD, PhD and Giuseppina Caligiuri, MD, PhD^_*,_*

^_* INSERM UMR S 872, Paris, France
INSERM UMR S 689, Paris, France
Department of Molecular Immunology, Medical University of Vienna, Vienna, Austria.

Manuscript received November 30, 2006; revised manuscript received March 22, 2007, accepted April 3, 2007.

^_* Reprint requests and correspondence: Dr. Giuseppina Caligiuri, INSERM UMR S 872, équipe 16, Les Cordeliers, 15, rue de l’Ecole de Médecine, Paris F-75006, France. (Email: giuseppina.caligiuri{at}umrs681.jussieu.fr).

Objectives: This study was designed to evaluate whether replacing CD31 (PECAM-1) signaling can restore the regulation of lymphocyte activation and improve experimental atherosclerosis.

Background: Atherosclerosis, the principal cause of myocardial infarction and stroke, is due to the development of a pathogenic immune response within the vascular wall and is aggravated by the reduction of regulatory T-cells. CD31, a transmembrane adhesion molecule with inhibitory signaling functions, is physiologically expressed on blood and vascular resting cells but is lost in pathologic conditions associated with atherosclerosis.

Methods: Replacement therapy with a CD31 receptor globulin (Rg) was delivered by in vivo gene transfer in 6-week-old apolipoprotein E knockout mice (n = 14 per group) every 5 weeks for 6 months. Control groups were treated with a truncated CD31Rg or with vehicle alone. At the end of the study, plaque size and morphology and blood T-cell compartment were analyzed in all mice.

Results: Atherosclerotic lesions of CD31Rg-treated mice were smaller (p < 0.01) and showed less neovascularization and intraplaque hemorrhage (p < 0.05) compared with control subjects. Furthermore, circulating regulatory T-cells were increased in vivo (p < 0.01) and showed normal suppressive function on proliferation of conventional T-cells in vitro. Indeed, CD31Rg treatment led to blunted blood T-cell activation (p < 0.05) and reduced T-cell infiltration within plaques (p < 0.01).

Conclusions: Our data suggest that CD31 plays a key role in the regulation of the immune response linked to atherosclerosis. CD31-targeting therapeutic approaches may therefore be envisaged for preventing and treating atherosclerotic diseases.

Abbreviations and Acronyms   CD31Rg = CD31 receptor globulin (domain 1-6)   CD31Rg 1-2 = truncated CD31 receptor globulin lacking domain 1-2 (domain 3-6)   HRP = horseradish peroxidase   Ig = immunoglobulin   MT = Masson’s trichrome staining   PBS = phosphate-buffered saline   Treg(s) = regulatory T-cell(s)