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- Gisterå, A., et al.
(författare)
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Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis
- 2017
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Ingår i: Journal of Internal Medicine. - : Wiley. - 0954-6820 .- 1365-2796. ; 281:4, s. 383-397
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Tidskriftsartikel (refereegranskat)abstract
- Background and Objectives: The T-cell response to low-density lipoprotein (LDL) in the vessel wall plays a critical role in atherosclerotic plaque formation and stability. In this study, we used a new translational approach to investigate epitopes from human apolipoprotein B100 (ApoB100), the protein component of LDL, which triggers T-cell activation. We also evaluated the potential of two selected native ApoB100 epitopes to modulate atherosclerosis in human ApoB100-transgenic Ldlr-/- (HuBL) mice. Methods and Results: HuBL mice were immunized with human atherosclerotic plaque homogenate to boost cellular autoimmune response to tissue-derived ApoB100 epitopes. In vitro challenge of splenocytes from immunized mice with a library of overlapping native peptides covering human ApoB100 revealed several sequences eliciting T-cell proliferation. Of these sequences, peptide (P) 265 and P295 were predicted to bind several human leucocyte antigen (HLA) haplotypes and induced high levels of interferon (IFN)-γ. Vaccination of HuBL mice with these peptides mounted a strong adaptive immune response to native ApoB100, including high levels of epitope-specific plasma IgGs. Interestingly, P265 and P295 vaccines significantly decreased plaque size, reduced macrophage infiltration and increased IgG1 deposition in the plaques. Purified IgGs from vaccinated mice displayed anti-inflammatory properties against macrophages in vitro, reducing their response to LPS in a dose-dependent manner. Conclusion: We identified two specific epitopes from human native ApoB100 that trigger T-cell activation and protect HuBL mice against atherosclerosis when used in a vaccine. Our data suggest that vaccination-induced protective mechanisms may be mediated at least in part through specific antibody responses to LDL that inhibit macrophage activation.
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| 2. |
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| 3. |
- Klingenberg, Roland, et al.
(författare)
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Depletion of FOXP3(+) regulatory T cells promotes hypercholesterolemia and atherosclerosis
- 2013
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Ingår i: Journal of Clinical Investigation. - 0021-9738 .- 1558-8238. ; 123:3, s. 1323-1334
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Tidskriftsartikel (refereegranskat)abstract
- Atherosclerosis is a chronic inflammatory disease promoted by hyperlipidemia. Several studies support FOXP3-positive regulatory T cells (Tregs) as inhibitors of atherosclerosis; however, the mechanism underlying this protection remains elusive. To define the role of FOXP3-expressing Tregs in atherosclerosis, we used the DEREG mouse, which expresses the diphtheria toxin (DT) receptor under control of the Treg-specific Foxp3 promoter, allowing for specific ablation of FOXP3(+) Tregs. Lethally irradiated, atherosclerosis-prone, low-density lipoprotein receptor-deficient (Ldlr(-/-)) mice received DEREG bone marrow and were injected with DT to eliminate FOXP3(+) Tregs. Depletion of Tregs caused a 2.1-fold increase in atherosclerosis without a concomitant increase in vascular inflammation. These mice also exhibited a 1.7-fold increase in plasma cholesterol and an atherogenic lipoprotein profile with increased levels of VLDL. Clearance of VLDL and chylomicron remnants was hampered, leading to accumulation of cholesterol-rich particles in the circulation. Functional and protein analyses complemented by gene expression array identified reduced protein expression of sortilin-1 in liver and increased plasma enzyme activity of lipoprotein lipase, hepatic lipase, and phospholipid transfer protein as mediators of the altered lipid phenotype. These results demonstrate that FOXP3(+) Tregs inhibit atherosclerosis by modulating lipoprotein metabolism.
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| 5. |
- Strodthoff, Daniela
(författare)
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Role of immune mediators in metabolic syndrome and atherosclerosis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Obesity is increasingly becoming a problem worldwide. Both location and metabolic activity of visceral and subcutaneous white adipose tissue (WAT) differ. Visceral fat is highly vascularized resulting in increased blood supply and increased infiltration of inflammatory immune cells such as macrophages, T cells and even B cells. Together with adipocytes these cells secrete adipokines/cytokines that propagate an inflammatory milieu locally as well as systemically. Obesity is strongly associated with the risk of cardiovascular disease (CVD) – diseases affecting the heart and the blood vessels. The underlying pathology of most CVDs is termed atherosclerosis, a chronic inflammatory condition of the arterial wall. The fatty streak formation is the first step in atherogenesis and is an accumulation of lipid-containing cells under the endothelial cell layer, which might progress to atheroma formation. Atherosclerotic lesions develop silently without symptoms over many years. This can change dramatically when a plaque raptures. Occlusion of the artery obstructing the blood flow may cause stroke, myocardial infarction or other life-threatening events. We demonstrate that inflammation of WAT can occur even in the absence of obesity. T cell-driven WAT inflammation and obesity-associated inflammation is characterized by increased T cell infiltration and expression of pro-inflammatory cytokines. Interestingly, IL-6 expression differs in the 2 forms of WAT (paper I). We further show the impact of liver-residing inflammatory iNKT cells on lipid metabolism, controlling metabolic processes distally in WAT (paper III). We also demonstrated the impact of the innate receptor TLR-3 on insulin secretion and lipid metabolism (paper IV). Changes in lipid metabolism and inflammation contribute to lesion development. Different strategies, including immune-modulation and even vaccination, are conceivable to prevent, stop or slow down lesion development. The project in my thesis that demonstrate the impact of FoxP3+ Tregs on lipid metabolism and atherosclerosis (paper II) encourages such work. Altogether, the findings in my thesis are based on in vitro and in vivo models of obesity and atherosclerosis, diseases that can promote each other’s development. We broke down the complex processes to study the involvement of single cell types (iNKT, FoxP3+ Tregs), receptors (TLR-3), and cytokines (IL-6). Together these approaches contribute to the understanding of the molecular mechanisms driving these diseases and will hopefully contribute to new therapeutic approaches.
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