Background and Aim
Atherosclerosis and its clinical complications, such as myocardial infarction and stroke represent the leading causes of mortality worldwide. Atherosclerosis is caused by a chronic inflammation of the vessel wall that is accompanied by a strong autoimmune response that involves auto-reactive T cells in lymph nodes and atherosclerotic plaques as well as autoantibodies that recognize low-density lipoprotein (LDL) and peptides from its main protein component Apolipoprotein B-100. Here, we investigate the potential of ApoB-specific vaccination to induce therapeutic immunomodulation of atherosclerosis in preclinical in vitro, in vivo and ex vivo models.
Results
Throughout the inflammatory response that accompanies experimental murine atherosclerosis, auto-reactive CD4+ T-helper cells accumulated in the atherosclerotic plaque. ApoB+ T-helper cells in lymph nodes contained a higher proportion of effector memory T cells (TEM, CD62L-CD44+) and central-memory T cells (TCM, CD62L+CD44+). The proportion of TEM-cells among ApoB+ T-helper cells was elevated in atherosclerosis-prone Apoe-/- mice compared with WT mice. This suggests that ApoB+ T-helper cells are activated under conditions of atherosclerosis. Likewise, we found that ApoB-reactive T-helper cells expand in the setting of atherosclerosis. Furthermore, ApoB+ FoxP3+ Tregs expressed higher levels of the atheroprotective cytokine IL-10 compared with ApoBneg Tregs suggesting a potential protective function of ApoB-reactive Tregs. Flourospot testing of T cells from atherosclerotic mice confirmed a IL-10 dominated cytokine signature of apoB-specific T cells. Vaccination with peptide ApoB induced a peptide- and site- specific T cell response in atherosclerotic mice and ameliorated de novo atherosclerosis in preclinical mouse models.
Conclusion
ApoB-specific vaccination has the potential to induce ApoB-specific regulatory CD4+ T cells that act anti-inflammatory likely by an IL-10 dependent mechanism.
