Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis
(2017) In Journal of Internal Medicine 281(4). p.383-397- 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... (More)
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.
(Less)
- author
- Gisterå, A. ; Hermansson, A. LU ; Strodthoff, Daniela ; Klement, M. L. LU ; Hedin, Ulf ; Fredrikson, G. N. LU ; Nilsson, J. LU ; Hansson, G. K. LU and Ketelhuth, Daniel F. J.
- organization
- publishing date
- 2017
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Apolipoprotein B-100, Atherosclerosis, Epitopes, T-cell, Vaccination
- in
- Journal of Internal Medicine
- volume
- 281
- issue
- 4
- pages
- 383 - 397
- publisher
- Wiley-Blackwell
- external identifiers
-
- pmid:28194913
- pmid:28194913
- wos:000397490100005
- scopus:85013116270
- ISSN
- 0954-6820
- DOI
- 10.1111/joim.12589
- language
- English
- LU publication?
- yes
- id
- 77199cb4-3a3d-4c6e-a6e4-ef36002bf574
- date added to LUP
- 2017-03-03 16:11:03
- date last changed
- 2024-11-26 06:18:30
@article{77199cb4-3a3d-4c6e-a6e4-ef36002bf574,
abstract = {{<p>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<sup>-/-</sup> (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.</p>}},
author = {{Gisterå, A. and Hermansson, A. and Strodthoff, Daniela and Klement, M. L. and Hedin, Ulf and Fredrikson, G. N. and Nilsson, J. and Hansson, G. K. and Ketelhuth, Daniel F. J.}},
issn = {{0954-6820}},
keywords = {{Apolipoprotein B-100; Atherosclerosis; Epitopes; T-cell; Vaccination}},
language = {{eng}},
number = {{4}},
pages = {{383--397}},
publisher = {{Wiley-Blackwell}},
series = {{Journal of Internal Medicine}},
title = {{Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis}},
url = {{http://dx.doi.org/10.1111/joim.12589}},
doi = {{10.1111/joim.12589}},
volume = {{281}},
year = {{2017}},
}