title: Naturally processed T cell epitopes from human glutamic acid decarboxylase identified using mice transgenic for the type 1 diabetes-associated human MHC class II allele, DRB1*0401.
abstract: The identification of class II binding peptide epitopes from autoimmune disease-related antigens is an essential step in the development of antigen-specific immune modulation therapy. In the case of type 1 diabetes, T cell and B cell reactivity to the autoantigen glutamic acid decarboxylase 65 (GAD65) is associated with disease development in humans and in nonobese diabetic (NOD) mice. In this study, we identify two DRB1*0401-restricted T cell epitopes from human GAD65, 274-286, and 115-127. Both peptides are immunogenic in transgenic mice expressing functional DRB1*0401 MHC class II molecules but not in nontransgenic littermates. Processing of GAD65 by antigen presenting cells (APC) resulted in the formation of DRB1*0401 complexes loaded with either the 274-286 or 115-127 epitopes, suggesting that these naturally derived epitopes may be displayed on APC recruited into pancreatic islets. The presentation of these two T cell epitopes in the islets of DRB1*0401 individuals who are at risk for type 1 diabetes may allow for antigen-specific recruitment of regulatory cells to the islets following peptide immunization.
authors.affiliation: Department of Autoimmune Diseases Research, Merck Research Laboratories, Rahway, New Jersey 07065-0900, USA. linda_wicker@merck.com
authors.forename: L S
authors.initials: LS
authors.lastname: Wicker
authors.forename: S L
authors.initials: SL
authors.lastname: Chen
authors.forename: G T
authors.initials: GT
authors.lastname: Nepom
authors.forename: J F
authors.initials: JF
authors.lastname: Elliott
authors.forename: D C
authors.initials: DC
authors.lastname: Freed
authors.forename: A
authors.initials: A
authors.lastname: Bansal
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.forename: A
authors.initials: A
authors.lastname: Herman
authors.forename: A
authors.initials: A
authors.lastname: Lernmark
authors.forename: D M
authors.initials: DM
authors.lastname: Zaller
authors.forename: L B
authors.initials: LB
authors.lastname: Peterson
authors.forename: J B
authors.initials: JB
authors.lastname: Rothbard
authors.forename: R
authors.initials: R
authors.lastname: Cummings
authors.forename: P J
authors.initials: PJ
authors.lastname: Whiteley
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000032:analysis*; D001402:B-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D000939:Epitopes / Q000032:analysis* / Q000737:chemistry; D005802:Genes, MHC Class II; D005968:Glutamate Decarboxylase / Q000096:biosynthesis / Q000276:immunology*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D059811:HLA-DRB1 Chains; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005968:Glutamate Decarboxylase