title: Modulation of recombinant antigenic constructs containing multi-epitopes towards effective reduction of atherosclerotic lesion in B6;129S-Ldlr(tm1Her)Apob(tm2Sgy)/J mice.
abstract: Atherosclerosis is increasingly recognized as a complex chronic inflammatory disease. Many more studies have extended vaccination against atherosclerosis by using epitopes from self-antigens or beyond and demonstrated that vaccination with antigens or derivatives could reduce the extent of the lesions in atherosclerosis-prone mice. Our previous study has demonstrated that construct AHHC [ApoB100688-707 + hHSP60303-312 + hHSP60153-163 + Cpn derived peptide (C)] significantly reduced atherosclerotic lesion. The aim of this study was to investigate whether AHHC can be modulated towards increased lesion reduction in mice by creating two other derivatives with a sequential epitope-substitution named RHHC in which A was replaced by an "R" (C5aR1-31) and RPHC with a further "H" (hHSP60303-312) conversion into "P" (protease-activated receptor-142-55) in mice. Antigenic epitopes were incorporated into a dendroaspin scaffold. Immunization of B6;129S-Ldlrtm1HerApobtm2Sgy/J mice with three constructs elicited production of high levels of antibodies against each epitope (apart from hHSP60153-163 and P which induced a low antibody response). Histological analyses demonstrated that the mice immunized with either RPHC or RHHC showed significant reductions in the size of atherosclerostic lesions compared to those with AHHC (69.5±1.1% versus 55.7±3.4%, P<0.01 or 65.6±1.3% versus 55.7±3.4%, P<0.01). Reduction of plaque size in the aortic sinus and descending aorta correlated with alterations in cellular immune responses when compared with controls. We conclude that a recombinant construct RPHC may provide new antigenic and structural features which are favorable for significant reduction in atherosclerotic lesion formation. This approach offers a novel strategy for developing anti-atherosclerotic agents.
authors.affiliation: The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London, United Kingdom.
authors.forename: Min
authors.initials: M
authors.lastname: Xia
authors.affiliation: The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London, United Kingdom; MRC Centre for Transplantation, King's College London, London, United Kingdom.
authors.forename: Daxin
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary.
authors.forename: Valeria
authors.initials: V
authors.lastname: Endresz
authors.affiliation: Department of Medical Microbiology and Immunobiology, University of Szeged, Szeged, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Lantos
authors.affiliation: Institute of Surgical Research, University of Szeged, Szeged, Hungary.
authors.forename: Andrea
authors.initials: A
authors.lastname: Szabo
authors.affiliation: The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London, United Kingdom; Thrombosis Research Institute, Bangalore, India.
authors.forename: Vijay
authors.initials: V
authors.lastname: Kakkar
authors.affiliation: The Mary and Garry Weston Molecular Immunology Laboratory, Thrombosis Research Institute, London, United Kingdom.
authors.forename: Xinjie
authors.initials: X
authors.lastname: Lu
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000941:Antigens / Q000276:immunology; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000276:immunology / Q000628:therapy*; D002454:Cell Differentiation; D002478:Cells, Cultured; D018920:Coculture Techniques; D000939:Epitopes / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D012850:Sinus of Valsalva / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014611:Vaccination; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
chemical_list: D000199:Actins; D000941:Antigens; C415826:Apob protein, mouse; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D000939:Epitopes; D007074:Immunoglobulin G; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D019010:Vascular Cell Adhesion Molecule-1; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
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