title: Identification of Candidate Tolerogenic CD8(+) T Cell Epitopes for Therapy of Type 1 Diabetes in the NOD Mouse Model.
abstract: Type 1 diabetes is an autoimmune disease in which insulin-producing pancreatic islet β cells are the target of self-reactive B and T cells. T cells reactive with epitopes derived from insulin and/or IGRP are critical for the initiation and maintenance of disease, but T cells reactive with other islet antigens likely have an essential role in disease progression. We sought to identify candidate CD8(+) T cell epitopes that are pathogenic in type 1 diabetes. Proteins that elicit autoantibodies in human type 1 diabetes were analyzed by predictive algorithms for candidate epitopes. Using several different tolerizing regimes using synthetic peptides, two new predicted tolerogenic CD8(+) T cell epitopes were identified in the murine homolog of the major human islet autoantigen zinc transporter ZnT8 (aa 158-166 and 282-290) and one in a non-β cell protein, dopamine β-hydroxylase (aa 233-241). Tolerizing vaccination of NOD mice with a cDNA plasmid expressing full-length proinsulin prevented diabetes, whereas plasmids encoding ZnT8 and DβH did not. However, tolerizing vaccination of NOD mice with the proinsulin plasmid in combination with plasmids expressing ZnT8 and DβH decreased insulitis and enhanced prevention of disease compared to vaccination with the plasmid encoding proinsulin alone.
authors.affiliation: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Cailin
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Jeremy C
authors.initials: JC
authors.lastname: Burns
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Geriatric Research Education and Clinical Center, Veterans Affairs, Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: William H
authors.initials: WH
authors.lastname: Robinson
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Utz
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Peggy P
authors.initials: PP
authors.lastname: Ho
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Steinman
authors.affiliation: Department of Cell Biology, New York University Langone School of Medicine, 550 First Avenue, New York, NY 10016, USA.
authors.forename: Alan B
authors.initials: AB
authors.lastname: Frey
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D027682:Cation Transport Proteins / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004299:Dopamine beta-Hydroxylase / Q000235:genetics / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007108:Immune Tolerance; D050417:Insulin-Secreting Cells / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation; D016688:Mice, Inbred NOD; D011384:Proinsulin / Q000235:genetics / Q000276:immunology*; D013997:Time Factors; D014611:Vaccination; D022223:Vaccines, Subunit / Q000235:genetics / Q000276:immunology; D014614:Vaccines, Synthetic / Q000235:genetics / Q000276:immunology; D000075703:Zinc Transporter 8
chemical_list: D001323:Autoantibodies; D027682:Cation Transport Proteins; D018984:Epitopes, T-Lymphocyte; C492522:SLC30A8 protein, human; D022223:Vaccines, Subunit; D014614:Vaccines, Synthetic; D000075703:Zinc Transporter 8; D011384:Proinsulin; D004299:Dopamine beta-Hydroxylase