Transgenically Induced GAD Tolerance Curtails the Development of Early -Cell Autoreactivities but Causes the Subsequent Development of Supernormal

RESEARCH DESIGN AND METHODS—We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other -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 1318 % of those in young NOD mice. This coincided with a great reduction in Th1 responses to other -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 -CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other -CAA–reactive T-cells to eventually ex-pand to a greater extent, perhaps by reducing competition fo