Regulating Inflammatory Immune Response to Atherogenic Antigens Prevents Development and Progression of Atherosclerosis in New Zealand White Rabbits.

BACKGROUND

Inflammatory immune response to atherogenic self-antigens plays an important role in the development of atherosclerosis. We evaluated the role of oral tolerance to three peptides in controlling atherosclerosis in New Zealand white rabbits.

METHODS

Peptides derived from apolipoprotein B (ApoB), heat shock protein 60, and outer membrane protein from Chlamydia pneumoniae were expressed as part of the dendroaspin protein scaffold (AHC). Groups of 3-month-old rabbits were dosed orally with purified AHC protein either before the onset of disease or 2 months after inducing atherosclerosis; they were euthanized at the age of 7 months to study disease development and progression.

RESULTS

Oral treatment with AHC resulted in a marked increase in regulatory T cells in the lymphoid organs and reduced the development and progression of atherosclerosis by 48.6% and 28.4%, respectively (P < 0.05). Oral tolerance decreased plaque inflammation, enhanced expression of anti-inflammatory and regulatory markers in the aorta, and attenuated the adaptive immune response to self-antigens. AHC treatment in rabbits with established disease significantly decreased vascular cell adhesion molecule 1 (VCAM-1) (6.2 fold) and monocyte chemoattractant protein-1(MCP-1) (3 fold) expression and reduced the infiltration of macrophages into the aorta. Collagen content and the smooth muscle cell-to-macrophage ratio were higher in treated animals, whereas markers of plaque vulnerability, including matrix metalloproteinase expression, were reduced.

CONCLUSIONS

Our results suggest that oral tolerance to multiantigenic AHC molecule restores the immune balance and induces markers of plaque stability in rabbits.