title: Immunization of HLA class I transgenic mice identifies autoantigenic epitopes eliciting dominant responses in type 1 diabetes patients.
abstract: Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells. CD8(+) T cells have recently been assigned a major role in beta cell injury. Consequently, the identification of autoreactive CD8(+) T cells in humans remains essential for development of therapeutic strategies and of assays to identify aggressive cells. However, this identification is laborious and limited by quantities of human blood samples available. We propose a rapid and reliable method to identify autoantigen-derived epitopes recognized by human CD8(+) T lymphocytes in T1D patients. Human histocompatibility leukocyte Ags-A*0201 (HLA-A*0201) transgenic mice were immunized with plasmids encoding the T1D-associated autoantigens: 65 kDa glutamic acid decarboxylase (GAD) or insulinoma-associated protein 2 (IA-2). Candidate epitopes for T1D were selected from peptide libraries by testing the CD8(+) reactivity of vaccinated mice. All of the nine-candidate epitopes (five for GAD and four for IA-2) identified by our experimental approach were specifically recognized by CD8(+) T cells from newly diagnosed T1D patients (n = 19) but not from CD8(+) T cells of healthy controls (n = 20). Among these, GAD(114-123), GAD(536-545) and IA-2(805-813) were recognized by 53%, 25%, and 42% of T1D patients, respectively.
authors.affiliation: Immuno-Endocrinology Unité Mixte de Recherche 707, Institut National de la Recherche Agronomique/Ecole Nationale Vétérinaire de Nantes/Université, Nantes, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Blancou
authors.forename: Roberto
authors.initials: R
authors.lastname: Mallone
authors.forename: Emanuela
authors.initials: E
authors.lastname: Martinuzzi
authors.forename: Sabine
authors.initials: S
authors.lastname: Sévère
authors.forename: Sylvie
authors.initials: S
authors.lastname: Pogu
authors.forename: Giulia
authors.initials: G
authors.lastname: Novelli
authors.forename: Graziella
authors.initials: G
authors.lastname: Bruno
authors.forename: Bernard
authors.initials: B
authors.lastname: Charbonnel
authors.forename: Manuel
authors.initials: M
authors.lastname: Dolz
authors.forename: Lucy
authors.initials: L
authors.lastname: Chaillous
authors.forename: Peter
authors.initials: P
authors.lastname: van Endert
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bach
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology*; D005260:Female; D005968:Glutamate Decarboxylase / Q000235:genetics / Q000276:immunology; D015234:HLA-A Antigens / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D016056:Immunodominant Epitopes / Q000276:immunology* / Q000378:metabolism; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000235:genetics / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000276:immunology; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
chemical_list: D001324:Autoantigens; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D016056:Immunodominant Epitopes; D007527:Isoenzymes; D008565:Membrane Proteins; D010446:Peptide Fragments; D019444:Vaccines, DNA; C516862:PTPRN protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017027:Protein Tyrosine Phosphatases; C516863:Ptprn protein, mouse; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2