title: Atheroprotective immunization with malondialdehyde-modified LDL is hapten specific and dependent on advanced MDA adducts: implications for development of an atheroprotective vaccine.
abstract: Immunization with homologous malondialdehyde (MDA)-modified LDL (MDA-LDL) leads to atheroprotection in experimental models supporting the concept that a vaccine to oxidation-specific epitopes (OSEs) of oxidized LDL could limit atherogenesis. However, modification of human LDL with OSE to use as an immunogen would be impractical for generalized use. Furthermore, when MDA is used to modify LDL, a wide variety of related MDA adducts are formed, both simple and more complex. To define the relevant epitopes that would reproduce the atheroprotective effects of immunization with MDA-LDL, we sought to determine the responsible immunodominant and atheroprotective adducts. We now demonstrate that fluorescent adducts of MDA involving the condensation of two or more MDA molecules with lysine to form malondialdehyde-acetaldehyde (MAA)-type adducts generate immunodominant epitopes that lead to atheroprotective responses. We further demonstrate that a T helper (Th) 2-biased hapten-specific humoral and cellular response is sufficient, and thus, MAA-modified homologous albumin is an equally effective immunogen. We further show that such Th2-biased humoral responses per se are not atheroprotective if they do not target relevant antigens. These data demonstrate the feasibility of development of a small-molecule immunogen that could stimulate MAA-specific immune responses, which could be used to develop a vaccine approach to retard or prevent atherogenesis.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Ayelet
authors.initials: A
authors.lastname: Gonen
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Lotte F
authors.initials: LF
authors.lastname: Hansen
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN.
authors.forename: William W
authors.initials: WW
authors.lastname: Turner
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Erica N
authors.initials: EN
authors.lastname: Montano
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Xuchu
authors.initials: X
authors.lastname: Que
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Apaїs
authors.initials: A
authors.lastname: Rafia
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Meng-Yun
authors.initials: MY
authors.lastname: Chou
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Philipp
authors.initials: P
authors.lastname: Wiesner
authors.affiliation: Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Tsiantoulas
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Maripat
authors.initials: M
authors.lastname: Corr
authors.affiliation: Department of Chemistry, Indiana University, Bloomington, IN.
authors.forename: Michael S
authors.initials: MS
authors.lastname: VanNieuwenhze
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Sotirios
authors.initials: S
authors.lastname: Tsimikas
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria Center for Molecular Medicine (CeMM) of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Christoph J
authors.initials: CJ
authors.lastname: Binder
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, CA Department of Biomedical Sciences, University of Copenhagen, Denmark.
authors.forename: Karsten
authors.initials: K
authors.lastname: Hartvigsen
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control; D006241:Haptens / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects / Q000235:genetics; D056724:Immunity, Humoral / Q000187:drug effects / Q000235:genetics; D007114:Immunization; D008077:Lipoproteins, LDL / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D008297:Male; D008315:Malondialdehyde / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology; D014612:Vaccines / Q000737:chemistry / Q000276:immunology / Q000494:pharmacology
chemical_list: D006241:Haptens; D008077:Lipoproteins, LDL; D014612:Vaccines; D008315:Malondialdehyde
keywords: adaptive immunity; humoral immunity; malondialdehyde-acetaldehyde adducts; oxidation-specific epitopes