title: Mycobacterial heat shock protein 65 (mbHSP65)-induced atherosclerosis: Preventive oral tolerization and definition of atheroprotective and atherogenic mbHSP65 peptides.
abstract: OBJECTIVE
  The aim of this study was to identify atherogenic and atheroprotective peptides of bacterial HSP60 [taking mycobacterial HSP65 (mbHSP65) as a potent paradigmatic representative] that could be used as candidates for an orally applied tolerizing vaccine against atherosclerosis.
  
  
  METHODS
  ApoE(-/-) mice were immunized with mbHSP65 protein or peptides, given mbHSP65 orally and then kept either on chow or high cholesterol diet. Atherosclerosis was assessed by en face and immunohistological analysis. Anti-HSP autoantibodies were detected by ELISA. The number and in vitro suppressive function of splenic and lymph node regulatory T cells (Tregs) were analyzed by flow cytometry. Specific T cell reactivity against mbHSP65 protein or peptides was assessed by proliferation assay.
  
  
  RESULTS
  Decreased lesion size was accompanied by (a) increased splenic Treg numbers; (b) increased interleukin (IL)-10 mRNA levels in the aorta; (c) increased levels of anti-mbHSP65 and anti-mouse HSP60 antibodies pointing to pro-eukaryotic HSP60 humoral crossreaction, not curtailed by oral tolerization; (d) most importantly, we identified and functionally characterized novel atherogenic and atheroprotective mbHSP65 epitopes.
  
  
  CONCLUSIONS
  Atheroprotective mbHSP65 peptides may be considered as potential candidates for the development of a tolerizing vaccine to prevent and treat atherosclerosis, while keeping protective immunity to non-atherogenic domains of mbHSP65 intact.
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria. Electronic address: Cecilia.Grundtman@i-med.ac.at.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Grundtman
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Bojana
authors.initials: B
authors.lastname: Jakic
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Maja
authors.initials: M
authors.lastname: Buszko
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Onestingel
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Almanzar
authors.affiliation: Department of Internal Medicine VI, Clinical Immunology and Infectious Diseases, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Egon
authors.initials: E
authors.lastname: Demetz
authors.affiliation: Central Laboratory Animal Facility, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Hermann
authors.initials: H
authors.lastname: Dietrich
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cappellano
authors.affiliation: Laboratory of Autoimmunity, Division for Experimental Pathophysiology and Immunology, Biocenter, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Georg
authors.initials: G
authors.lastname: Wick
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D001011:Aorta / Q000187:drug effects / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000097:blood; D001426:Bacterial Proteins / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D018834:Chaperonin 60 / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity; D002791:Cholesterol, Dietary; D003429:Cross Reactions; D004195:Disease Models, Animal; D018604:Epitope Mapping; D000939:Epitopes; D005260:Female; D007114:Immunization; D007279:Injections, Subcutaneous; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000276:immunology; D013154:Spleen / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D022223:Vaccines, Subunit / Q000008:administration & dosage* / Q000276:immunology / Q000633:toxicity
chemical_list: D000907:Antibodies, Bacterial; D001057:Apolipoproteins E; D001323:Autoantibodies; D001426:Bacterial Proteins; D018834:Chaperonin 60; D002791:Cholesterol, Dietary; D000939:Epitopes; C557066:Hspd1 protein, mouse; C556062:IL10 protein, mouse; D024101:Mitochondrial Proteins; D022223:Vaccines, Subunit; C074119:heat-shock protein 65, Mycobacterium; D016753:Interleukin-10
keywords: Atherosclerosis; Heat shock protein; Inflammation; Peptide; Treatment