title: Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance.
abstract: We have shown previously that collagen V (col(V)) autoimmunity is a consistent feature of atherosclerosis in human coronary artery disease and in the Apoe(-/-) mouse model. We have also shown sensitization of Apoe(-/-) mice with col(V) to markedly increase the atherosclerotic burden, providing evidence of a causative role for col(V) autoimmunity in atherosclerotic pathogenesis. Here we sought to determine whether induction of immune tolerance to col(V) might ameliorate atherosclerosis, providing further evidence for a causal role for col(V) autoimmunity in atherogenesis and providing insights into the potential for immunomodulatory therapeutic interventions. Mucosal inoculation successfully induced immune tolerance to col(V) with an accompanying reduction in plaque burden in Ldlr(-/-) mice on a high-cholesterol diet. The results therefore demonstrate that inoculation with col(V) can successfully ameliorate the atherosclerotic burden, suggesting novel approaches for therapeutic interventions. Surprisingly, tolerance and reduced atherosclerotic burden were both dependent on the recently described IL-35 and not on IL-10, the immunosuppressive cytokine usually studied in the context of induced tolerance and amelioration of atherosclerotic symptoms. In addition to the above, using recombinant protein fragments, we were able to localize two epitopes of the α1(V) chain involved in col(V) autoimmunity in atherosclerotic Ldlr(-/-) mice, suggesting future courses of experimentation for the characterization of such epitopes.
authors.affiliation: From the Departments of Cell and Regenerative Biology and.
authors.forename: Arick C
authors.initials: AC
authors.lastname: Park
authors.affiliation: From the Departments of Cell and Regenerative Biology and.
authors.forename: Guorui
authors.initials: G
authors.lastname: Huang
authors.affiliation: Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705.
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Gan
authors.affiliation: From the Departments of Cell and Regenerative Biology and.
authors.forename: Dawiyat
authors.initials: D
authors.lastname: Massoudi
authors.affiliation: From the Departments of Cell and Regenerative Biology and.
authors.forename: John F
authors.initials: JF
authors.lastname: Kernien
authors.affiliation: the Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, the Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, and.
authors.forename: Dario A
authors.initials: DA
authors.lastname: Vignali
authors.affiliation: Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705.
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Sullivan
authors.affiliation: the Center for Immunobiology, Departments of Medicine and Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: David S
authors.initials: DS
authors.lastname: Wilkes
authors.affiliation: Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53705.
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.affiliation: From the Departments of Cell and Regenerative Biology and dsgreens@wisc.edu.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Greenspan
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D057134:Antibodies, Neutralizing / Q000008:administration & dosage / Q000378:metabolism; D050197:Atherosclerosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D015551:Autoimmunity; D002417:Cattle; D002478:Cells, Cultured; D024062:Collagen Type V / Q000008:administration & dosage / Q000737:chemistry / Q000235:genetics / Q000627:therapeutic use*; D066273:Diet, Western / Q000009:adverse effects; D018604:Epitope Mapping; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D007108:Immune Tolerance; D018928:Immunity, Mucosal; D007378:Interleukins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology
chemical_list: D057134:Antibodies, Neutralizing; C530725:COL5A1 protein, human; D024062:Collagen Type V; D007378:Interleukins; D010446:Peptide Fragments; D011973:Receptors, LDL; D011994:Recombinant Proteins; C569375:interleukin-35, mouse
keywords: IL-35; atherosclerosis; autoimmune disease; autoimmunity; collagen type V; immunotherapy; vascular smooth muscle cells