Abstract
Oral tolerance to auto antigens reduces the development of atherosclerosis in mouse models. However, the effect of immune tolerance to multiple self antigenic peptides in plaque progression and stabilization is not known. We studied the protective effect of mucosal tolerance to peptides from apolipoprotein B (ApoB; 661–680) and heat shock protein 60 (HSP60; 153–163), in combination with diet, in the prevention of atherosclerotic lesion progression and plaque stabilization in ApoBtm25gyLDLrtm1Her mice. We found that oral administration of five doses of a combination of ApoB and HSP60 peptides (20 µg/mice/dose) induced tolerance to both the peptides and reduced early plaque development by 39.9% better than the individual peptides (ApoB = 28.7%;HSP60 = 26.8%)(P<0.001). Oral tolerance to combination of peptides along with diet modification arrested plaque progression by 37.6% which was associated with increases in T-regulatory cell and transforming growth factor-β expression in the plaque and peripheral circulation. Reduced macrophage infiltration and tumor necrosis factor-α expression in the plaque was also observed. Tolerance with continued hypercholesterolemia resulted in 60.8% reduction in necrotic core area suggesting plaque stabilization, which was supported by reduction in apoptosis and increased efferocytosis demonstrated by greater expression of receptor tyrosine kinase Mer (MerTK) in the plaque. Tolerance to the two peptides also reduced the expression of matrix metalloproteinase 9, tissue factor, calprotectin, and increased its collagen content. Our study suggests that oral tolerance to ApoB and HSP60 peptide combination induces CD4+ CTLA4+ Tregs and CD4+CD25+Foxp3+ Tregs secreting TGF-β, which inhibit pathogenic T cell response to both peptides thus reducing the development and progression of atherosclerosis and provides evidence for plaque stabilization in ApoBtm25gyLDLrtm1Her mice.
Highlights
Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by accumulation of lipids and immune inflammatory cells [1,2,3]
Individual treatment with apolipoprotein B (ApoB) and heat shock protein 60 (HSP60) peptides reduced early lesion development by 28.7%, and 26.8%, respectively, while the combination of two peptides resulted in a significant reduction in atherosclerotic lesion in aortic root (39.9%, P,0.001) (Figure 1B)
We observed a reduction in TUNEL positivity in the peptide-tolerized mice (Figure S7).We examined the nature of cells which are undergoing apoptosis in the advanced lesion by double immuno staining for macrophages and smooth muscle cells (SMC) along with anti caspase3 antibodies
Summary
Atherosclerosis is a chronic inflammatory disease of the arterial wall characterized by accumulation of lipids and immune inflammatory cells [1,2,3]. Inflammation mediated by a pathogenic T-cell response to autologous antigens like modified low density lipoproteins (LDL) and heat shock proteins (HSP) as well as exogenous antigens from pathogens, have been implicated in the initiation of an autoimmune response during atherogenesis [4,5,6,7,8]. It was shown that HSP60reactive T-cells can initiate atherosclerosis by recognizing atherogenic HSP60 epitopes in the intima [9]. Retention of LDL in the arteries and its modification are early events during atherogenesis which expose neo epitopes from ApoB 100 and Oxidized LDL, initiating inflammatory adaptive T cell response [7,10]. Pro inflammatory Th1 response to these antigens predominates during the progression of the disease
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