This article is part of the Research Topic Proceedings of ICI Milan 2013

Original Research ARTICLE

Front. Immunol., 27 December 2013 | doi: 10.3389/fimmu.2013.00493

Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100

imageKevin Tse1,2*, imageAyelet Gonen3, imageJohn Sidney4, imageHui Ouyang2, imageJoseph L. Witztum3, imageAlessandro Sette4, imageHarley Tse5 and imageKlaus Ley2
  • 1Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California at San Diego, La Jolla, CA, USA
  • 2Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
  • 3Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego, La Jolla, CA, USA
  • 4Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA
  • 5Department of Immunology and Microbiology, School of Medicine, Wayne State University, Detroit, MI, USA

Background: Subsets of CD4+ T-cells have been proposed to serve differential roles in the development of atherosclerosis. Some T-cell types are atherogenic (T-helper type 1), while others are thought to be protective (regulatory T-cells). Lineage commitment toward one type of helper T-cell versus another is strongly influenced by the inflammatory context in which antigens are recognized. Immunization of atherosclerosis-prone mice with low-density lipoprotein (LDL) or its oxidized derivative (ox-LDL) is known to be atheroprotective. However, the antigen specificity of the T-cells induced by vaccination and the mechanism of protection are not known.

Methods: Identification of two peptide fragments (ApoB3501–3516 and ApoB978–993) from murine ApoB-100 was facilitated using I-Ab prediction models, and their binding to I-Ab determined. Utilizing a vaccination scheme based on complete and incomplete Freund’s adjuvant (CFA and IFA) [1 × CFA + 4 × IFA], we immunized Apoe−/−mice with ApoB3501–3516 or ApoB978–993 emulsified in CFA once and subsequently boosted in IFA four times over 15 weeks. Spleens, lymph nodes, and aortas were harvested and evaluated by flow cytometry and real time RT-PCR. Total atherosclerotic plaque burden was determined by aortic pinning and by aortic root histology.

Results: Mice immunized with ApoB3501–3516 or ApoB978–993 demonstrated 40% reduction in overall plaque burden when compared to adjuvant-only control mice. Aortic root frozen sections from ApoB3501–3516 immunized mice showed a >60% reduction in aortic sinus plaque development. Aortas from both ApoB3501–3516 and ApoB978–993 immunized mice contained significantly more mRNA for IL-10. Both antigen-specific IgG1 and IgG2c titers were elevated in ApoB3501–3516 or ApoB978–993 immunized mice, suggesting helper T-cell immune activity after immunization.

Conclusion: Our data show that MHC Class II restricted ApoB-100 peptides can be atheroprotective, potentially through a mechanism involving elevated IL-10.

Keywords: T-cell, atherosclerosis, vaccination, inflammation

Citation: Tse K, Gonen A, Sidney J, Ouyang H, Witztum JL, Sette A, Tse H and Ley K (2013) Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100. Front. Immunol. 4:493. doi: 10.3389/fimmu.2013.00493

Received: 12 November 2013; Accepted: 16 December 2013;
Published online: 27 December 2013.

Edited by:

Francesca Di Rosa, Italian National Research Council, Italy

Reviewed by:

Gregory B. Lesinski, The Ohio State University Comprehensive Cancer Center, USA
Ennio De Gregorio, Novartis Vaccines and Diagnostics, Italy

Copyright: © 2013 Tse, Gonen, Sidney, Ouyang, Witztum, Sette, Tse and Ley. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Kevin Tse, Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California at San Diego, 9420 Athena Cir, MC 0859, La Jolla, CA 92037, USA e-mail: ktse@liai.org

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