title: Oral dosing with multi-antigenic construct induces atheroprotective immune tolerance to individual peptides in mice.
abstract: Inflammatory immune response to self-antigens plays an important role in the development of atherosclerosis. Restoring immune tolerance to self-proteins reduces the pro-inflammatory response. We previously showed that oral tolerance to a combination of two peptides is atheroprotective. In the present study we expressed epitopes from apolipoprotein B 100 (ApoB), human heat shock protein (HSP60) and Chlamydia pneumonia outer membrane protein (Cpn) in a single protein scaffold and used this multi-antigenic construct to induce tolerance to individual peptides by oral route in ApoBtm2Sgy/Ldlrtm1Her/J mice. Antigen specific tolerance to individual peptides was observed in treated animals as seen by an increase in regulatory T cells. Tolerance to the peptides resulted in a 46.5% (p=0.002) reduction in the development of atherosclerosis compared with control. Atheroprotection was associated with a significant (p<0.05) decrease in plaque inflammation and an increase in the expression of immune regulatory markers in the aorta. CD11c+ cells coexpressing CD11b and CD103 increased in lymphoid organs and were found to activate regulatory T cells and reduce effector T-cell response. Adoptive transfer of CD11c+ cells was atheroprotective. Our results suggest that atheroprotection by oral tolerance to a multi-antigenic construct is mediated by antigen specific regulatory T cells and CD11c+ cells with immune regulatory properties.
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India. Electronic address: lakshmi.mundkur@triindia.org.in.
authors: Lakshmi
authors: L
authors: Mundkur
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India.
authors: Thiruvelselvan
authors: T
authors: Ponnusamy
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India.
authors: Sheena
authors: S
authors: Philip
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India.
authors: Lakshmi Narasimha
authors: LN
authors: Rao
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India.
authors: Suryakant
authors: S
authors: Biradar
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India.
authors: Vrushali
authors: V
authors: Deshpande
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India.
authors: Ramesh
authors: R
authors: Kumar
authors: Molecular Immunology Unit, Thrombosis Research Institute, London, United Kingdom.
authors: Xinjie
authors: X
authors: Lu
authors: Mary and Gary Western and Tata Molecular Immunology Unit, Thrombosis Research Institute, Bangalore, India; Molecular Immunology Unit, Thrombosis Research Institute, London, United Kingdom. Electronic address: president@tri-kakkar.ch.
authors: Vijay V
authors: VV
authors: Kakkar
mesh_terms: D000284:Administration, Oral; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000276:immunology*; D018834:Chaperonin 60 / Q000008:administration & dosage; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D024101:Mitochondrial Proteins / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D018834:Chaperonin 60; C060293:HSPD1 protein, human; D024101:Mitochondrial Proteins; D010446:Peptide Fragments
keywords: Atherosclerosis; Dendritic cells; Immune tolerance; Inflammation; Vaccine