title: Atheroprotective Vaccination with MHC-II Restricted Peptides from ApoB-100.
abstract: 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.
  
  
  CONCLUSIONS
  Our data show that MHC Class II restricted ApoB-100 peptides can be atheroprotective, potentially through a mechanism involving elevated IL-10.
authors.affiliation: Department of Medicine, Division of Rheumatology, Allergy and Immunology, University of California at San Diego , La Jolla, CA , USA ; Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA , USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Tse
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego , La Jolla, CA , USA.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA , USA.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA , USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Ouyang
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California at San Diego , La Jolla, CA , USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology , La Jolla, CA , USA.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.affiliation: Department of Immunology and Microbiology, School of Medicine, Wayne State University , Detroit, MI , USA.
authors.forename: Harley
authors.initials: H
authors.lastname: Tse
authors.affiliation: Division of Inflammation Biology, La Jolla Institute for Allergy and Immunology , La Jolla, CA , USA.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
keywords: T-cell; atherosclerosis; inflammation; vaccination