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(Circulation. 2006;114:1977-1984.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Short-Term Treatment With Anti-CD3 Antibody Reduces the Development and Progression of Atherosclerosis in Mice

Sabine Steffens, PhD; Fabienne Burger, Bsc; Graziano Pelli, Bsc; Yann Dean, PhD; Greg Elson, PhD; Marie Kosco-Vilbois, PhD; Lucienne Chatenoud, MD; François Mach, MD

From the Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, Geneva, Switzerland (S.S., F.B., G.P., F.M.); NovImmune SA, Geneva, Switzerland (Y.D., G.E., M.K.-V.); and INSERM U580, Hôpital Necker, Paris, France (L.C.).

Correspondence to François Mach, Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland. E-mail Francois.Mach{at}medecine.unige.ch

Received March 16, 2006; revision received July 7, 2006; accepted July 28, 2006.

Background— Atherosclerosis is a chronic inflammatory disease of the large arteries that is the primary cause of heart disease and stroke. Anti-CD3–specific antibodies suppress immune responses by antigenic modulation of the CD3 antibody/T-cell receptor complex. Their unique capacity to restore self-tolerance in a mouse model of diabetes and, importantly, in patients with recent-onset type 1 diabetes involves transforming growth factor-ß–dependent mechanisms via expansion and/or activation of regulatory T cells. We hypothesized that treatment with anti-CD3–specific antibodies might inhibit atherosclerosis development and progression in mice.

Methods and Results— Low-density lipoprotein receptor–deficient mice were fed a high-cholesterol diet for 13 or 24 weeks. Anti-CD3 antibody was administered on 5 consecutive days beginning 1 week before or 13 weeks after the high-cholesterol diet was initiated, respectively. Control mice were injected in parallel with phosphate-buffered saline. Anti-CD3 antibody therapy reduced plaque development when administered before a high-cholesterol diet and markedly decreased lesion progression in mice with already established atherosclerosis. We found increased production of the antiinflammatory cytokine transforming growth factor-ß in concanavalin A–stimulated lymph node cells and enhanced expression of the regulatory T-cell marker Foxp3 in spleens of anti-CD3 antibody–treated mice. A higher percentage of apoptotic cells within the plaques of anti-CD3 antibody–treated mice was also observed.

Conclusions— Altered disease progression, combined with the emergence of this particular cytokine pattern, indicates that short-term treatment with an anti-CD3 antibody induces a regulatory T-cell phenotype that restores self-tolerance in a mouse model of atherosclerosis.

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