Treatment with apo B peptide vaccines inhibits atherosclerosis in human apo B-100 transgenic mice without inducing an increase in peptide-specific antibodies.

Abstract

OBJECTIVES: Autoantibodies to apolipoprotein (apo) B-100 peptides are present in human plasma and have been shown to be associated with decreased cardiovascular risk. The present study aimed to determine if apo B-100 peptide vaccines are atheroprotective in mice expressing human apo B-100 and if the effectiveness of the vaccines is influenced by the level of pre-existing peptide-specific autoantibodies. DESIGN: LDL receptor(-/-)/human apo B-100 transgenic mice were immunized with native human apo B-100 peptides p45 or p210 at 6, 9 and 11 weeks and the extent of atherosclerosis determined by en face Oil Red O staining of the aorta at 25 weeks. Autoantibody levels were determined by enzyme-linked immunosorbent assay, and RNA expression in the spleen was assessed by real time PCR. RESULTS: Control mice had high levels of autoantibodies against p210 but only low levels against p45. Immunization with native p45 and p210 reduced atherosclerosis by 66% (P < 0.02) and 59% (P = 0.06), respectively. The atheroprotective effect of apo B peptide immunization occurred in the absence of an increase in peptide-specific IgG, but was associated with an increase in IgM recognizing native and copper-oxidized LDL. CONCLUSIONS: Immunization with apo B peptide-based vaccines inhibits atherosclerosis in mice expressing human apo B-100 suggesting that they can interact with their target as expressed in humans. The protective effect is independent of the pre-existing level of apo B peptide autoantibodies and can occur without activating an increase in peptide-specific antibodies suggesting that atheroprotection can be mediated by cellular immune responses.