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

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. (2017) In Journal of Internal Medicine1989-01-01+01:00 281(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.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Apolipoprotein B-100, Atherosclerosis, Epitopes, T-cell, Vaccination
in
Journal of Internal Medicine1989-01-01+01:00
volume
281
issue
4
pages
383 - 397
publisher
Wiley-Blackwell Publishing Ltd
external identifiers
  • scopus:85013116270
  • pmid:28194913
  • wos:000397490100005
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
2018-05-20 04:32:12
@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},
  keyword      = {Apolipoprotein B-100,Atherosclerosis,Epitopes,T-cell,Vaccination},
  language     = {eng},
  number       = {4},
  pages        = {383--397},
  publisher    = {Wiley-Blackwell Publishing Ltd},
  series       = {Journal of Internal Medicine1989-01-01+01:00},
  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},
  volume       = {281},
  year         = {2017},
}