| First Author | Tian J | Year | 2009 |
| Journal | Diabetes | Volume | 58 |
| Issue | 12 | Pages | 2843-50 |
| PubMed ID | 19741165 | Mgi Jnum | J:158247 |
| Mgi Id | MGI:4438321 | Doi | 10.2337/db08-0851 |
| Citation | Tian J, et al. (2009) 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. Diabetes 58(12):2843-50 |
| abstractText | 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. RESEARCH DESIGN AND 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. |
