Oral dosing with multi-antigenic construct induces atheroprotective immune tolerance to individual peptides in mice

- Peptides from ApoB, HSP60 and C pneumonia expressed in a muti-antigenic construct.
- Oral administration of multi antigenic construct induced peptide specific tolerance.
- Tolerance to peptides reduced atherosclerosis by 46.5 % in the aortic sinus.
- Atheroprotection was associated with reduced plaque inflammation.
- Adoptive transfer of CD11c+ cells was atheroprotective.

Inflammatory immune response to self-antigens plays an important role in the development of atherosclerosis. Restoring immune tolerance to self-proteins reduces the pro-inflammatory response. We previously showed that oral tolerance to a combination of two peptides is atheroprotective. In the present study we expressed epitopes from apolipoprotein B 100 (ApoB), human heat shock protein (HSP60) and Chlamydia pneumonia outer membrane protein (Cpn) in a single protein scaffold and used this multi-antigenic construct to induce tolerance to individual peptides by oral route in ApoBtm2Sgy/Ldlrtm1Her/J mice. Antigen specific tolerance to individual peptides was observed in treated animals as seen by an increase in regulatory T cells. Tolerance to the peptides resulted in a 46.5% (p = 0.002) reduction in the development of atherosclerosis compared with control. Atheroprotection was associated with a significant (p < 0.05) decrease in plaque inflammation and an increase in the expression of immune regulatory markers in the aorta. CD11c+ cells coexpressing CD11b and CD103 increased in lymphoid organs and were found to activate regulatory T cells and reduce effector T-cell response. Adoptive transfer of CD11c+ cells was atheroprotective. Our results suggest that atheroprotection by oral tolerance to a multi-antigenic construct is mediated by antigen specific regulatory T cells and CD11c+ cells with immune regulatory properties.