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Prof. Lale Tokgozoglu,
The role of the immune system in atherosclerosis development was examined closely in this session. Dr Binder started the session by exploring the innate responses of the immune system as a potential therapeutic intervention for atherosclerosis. He explained that oxidation specific epitopes are danger associated molecular patterns which are recognised by pattern recognition receptors of innate immunity and are thus targets for innate immunity. Innate immunity consists of natural antibodies that are secreted by B1 cells and are primarily Ig M. Previous studies have shown that anti-oxidised LDL IgM antibodies are related to decreased coronary stenosis. These antibodies bind to oxidation epitopes and are present in several other autoimmune diseases. Deficency of IgM has been demonstrated to increase atherosclerosis in mice models. Dr Binder also discussed the antiatherosclerotic effects of IL-13 saying that IL-13 increases the clearance of oxidised LDL by macrophages, promotes plaque stabilisation and its deficency promotes atherosclerosis in mice. He concluded that a number of protective functions like the innate immunity have important homeostatic functions that regulate and prevent accumulation of cells in the atherosclerotic lesion and clear debris but become insufficent in circumstances of increased oxidative stress. Dr. Hansson first explained that the atherosclerotic plaque was a site of immune inflammation containing both innate and adaptive immunity and the dendritic cells were a bridge between adaptive and innate immunity. The dendritic cells patrol the artery, move to lymph nodes and activate naive T cells determining their fate. Under some circumstances, dendritic cells instruct the T cells to calm down. These cells operate by cell surface molecules, costimulation, cytokines and metabolites. An important metabolite is indoleamine2,3 dioxygenase (IDO) which upregulates regulatory T cells via a tryptophan metabolite called 3-hydroxyanthranilic acid (3-HAA) . It has been shown that 3-HAA protects LDL receptor mice from atherosclerosis, reduces vascular inflammation and inhibits oxidised LDL uptake by peritoneal macrophages. Interestingly, it also has lipid lowering activity and affects genes in lipid metabolism. Therefore, this metabolite has important antiatherosclerotic activities and may have potential therapeutic implications. Dr Ait-Oufella overviewed the role of the B cell in atherogenesis.He explained the difference between B1 and B2 cells, the importance of B1 cells in innate immunity and the atheroprotective effects of natural IgM. He gave detailed information about B1 cells regulating natural IgM, which has a role in apoptotic cell clearance thus antiatherosclerotic effects , and the B2 cells regulating the T cells and their proatherosclerotic effects. Dr. Nilsson gave a detailed insight into immunisation for atherosclerosis. He explained that loss of immunological tolerance against plaque antigens results in proinflammatory autoimmunity and that inflammation makes it difficult for the immune system to differentiate between self and nonself. He explained that oxidised LDL was the key antigen, but there were others, including LDL.The main targets in LDL are peptide sequences in apoprotein B (apoB), like P210, P45 and P2. ApoB peptide vaccines including these peptides in their formulation were formed. These vaccines or infusion of these peptides increased regulatory T cells, reduced atherosclerotic lesion size in mice and induced IL-10 producing CD4+ T cells. There are studies showing that high levels of IgG against these peptides are associated with decreased risk of MI and coronary artery disease. The apoB peptide atherosclerosis vaccine reduces atherosclerosis in animal models, is effective subcutaneously and by mucosal administration and preclinical safety studies are ongoing. There are challenges about whether this will be as effective in humans, biomarkers to measure the effect of the vaccine, HLA matching and safety issues.
Interfering with the immune system in atherosclerosis: therapies of the future?
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