Published online before print October 16, 2006, doi: 10.1161/CIRCULATIONAHA.106.627430
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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
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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