title: Transgenically induced GAD tolerance curtails the development of early beta-cell autoreactivities but causes the subsequent development of supernormal autoreactivities to other beta-cell antigens.
abstract: OBJECTIVE
  To study how tolerance to GAD65 affects the development of autoimmunity to other beta-cell autoantigens (beta-CAAs) in GAD65-transgenic (GAD-tg) NOD mice.
  
  
  METHODS
  We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other beta-CAAs at different ages in GAD-tg mice and their NOD mouse littermates.
  
  
  RESULTS
  In young GAD-tg mice, Th1 responses to GAD65's dominant determinants were 13-18% of those in young NOD mice. This coincided with a great reduction in Th1 responses to other beta-CAAs. Evidently, GAD65-reactive T-cells are important for activating and/or expanding early autoreactivities in NOD mice. As GAD-tg mice aged, their T-cell responses to GAD65 remained low, but they developed supernormal splenic and pancreatic lymph node T-cell autoimmunity to other beta-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other beta-CAA-reactive T-cells to eventually expand to a greater extent, perhaps by reducing competition for antigen-presenting cells, or homeostatic proliferation in the target tissue, which may explain the GAD-tg mouse's usual disease incidence.
  
  
  CONCLUSIONS
  Transgenically induced reduction of GAD65 autoreactivity curtailed the development of early T-cell responses to other beta-CAAs. However, later in life, beta-CAA-reactive T-cells expanded to supernormal levels. These data suggest that early beta-cell autoreactivities are mutually dependent for support to activate and expand, while later in the disease process, autoantigen-specific T-cell pools can expand autonomously. These findings have implications for understanding type 1 diabetes immunopathogenesis and for designing antigen-based immunotherapeutics.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California-Los Angeles, Los Angeles, California, USA.
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.forename: Hoa
authors.initials: H
authors.lastname: Dang
authors.forename: Harald
authors.initials: H
authors.lastname: von Boehmer
authors.forename: Elmar
authors.initials: E
authors.lastname: Jaeckel
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kaufman
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D005968:Glutamate Decarboxylase / Q000276:immunology* / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010179:Pancreas / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001324:Autoantigens; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; C401141:glutamate decarboxylase 2