title: Vaccination against T-cell epitopes of native ApoB100 reduces vascular inflammation and disease in a humanized mouse model of atherosclerosis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Gisterå
authors.affiliation: Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Hermansson
authors.affiliation: Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Strodthoff
authors.affiliation: Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: M L
authors.initials: ML
authors.lastname: Klement
authors.affiliation: Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institute, Stockholm, Sweden.|Department of Vascular Surgery, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: U
authors.initials: U
authors.lastname: Hedin
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: G N
authors.initials: GN
authors.lastname: Fredrikson
authors.affiliation: Department of Clinical Sciences, Skåne University Hospital, Lund University, Malmö, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Nilsson
authors.affiliation: Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: G K
authors.initials: GK
authors.lastname: Hansson
authors.affiliation: Department of Medicine, Cardiovascular Medicine Unit, Center for Molecular Medicine, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: D F J
authors.initials: DF
authors.lastname: Ketelhuth
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000276:immunology* / Q000378:metabolism; D050197:Atherosclerosis / Q000276:immunology* / Q000517:prevention & control*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006681:HLA-D Antigens / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis; D007249:Inflammation / Q000517:prevention & control; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D058226:Plaque, Atherosclerotic / Q000276:immunology; D014611:Vaccination
chemical_list: D053299:Apolipoprotein B-100; D018984:Epitopes, T-Lymphocyte; D006681:HLA-D Antigens; D007074:Immunoglobulin G
keywords: T-cell; apolipoprotein B-100; atherosclerosis; epitopes; vaccination