Short-term treatment with anti-CD3 antibody reduces the development and progression of atherosclerosis in mice.
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-beta-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.


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-beta 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.
Steffens
Sabine
S
Division of Cardiology, Department of Medicine, University Hospital, Foundation for Medical Researches, 64 Avenue Roseraie, 1211 Geneva, Switzerland.
Burger
Fabienne
F
Pelli
Graziano
G
Dean
Yann
Y
Elson
Greg
G
Kosco-Vilbois
Marie
M
Chatenoud
Lucienne
L
Mach
François
F
D000818:Animals; D000906:Antibodies / Q000627:therapeutic use*; D017209:Apoptosis; D050197:Atherosclerosis / Q000188:drug therapy / Q000517:prevention & control / Q000628:therapy*; D017252:CD3 Complex / Q000276:immunology* / Q000378:metabolism; D018450:Disease Progression; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017260:Receptor-CD3 Complex, Antigen, T-Cell / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000096:biosynthesis
D000906:Antibodies; D017252:CD3 Complex; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D017260:Receptor-CD3 Complex, Antigen, T-Cell; D011973:Receptors, LDL; D016212:Transforming Growth Factor beta