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J Intern Med. 2017 Apr;281(4):383-397. doi: 10.1111/joim.12589. Epub 2017 Feb 13.

Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis.

Author information

1
Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
2
Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.
3
Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.
4
Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.

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.

KEYWORDS:

T-cell; apolipoprotein B-100; atherosclerosis; epitopes; vaccination

PMID:
28194913
DOI:
10.1111/joim.12589
[Indexed for MEDLINE]

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