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

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

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Title: Transgenically Induced GAD Tolerance Curtails the Development of Early β-Cell Autoreactivities but Causes the Subsequent Development of Supernormal Autoreactivities to Other β-Cell Antigens
Author: Tian, Jide; Dang, Hoa; Jaeckel, Elmar; Kaufman, Daniel L.; von Boehmer, Harald

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Citation: Tian, Jide, Hoa Dang, Harald von Boehmer, Elmar Jaeckel, and Daniel L. Kaufman. 2009. Transgenically induced GAD tolerance curtails the development of early β-cell autoreactivities but causes the subsequent development of supernormal autoreactivities to other β-cell antigens. Diabetes 58(12): 2843-2850.
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Abstract: Objective: To study how tolerance to GAD65 affects the development of autoimmunity to other β-cell autoantigens (β-CAAs) in GAD65-transgenic (GAD-tg) NOD mice. Research Designs and Methods: We used ELISPOT to characterize the frequency and functional phenotype of T-cell responses to GAD65 and other β-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 β-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 β-CAAs. Apparently, the elimination/impairment of many GAD65-reactive T-cells allowed other β-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 β-CAAs. However, later in life, β-CAA–reactive T-cells expanded to supernormal levels. These data suggest that early β-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.
Published Version: doi://10.2337/db08-0851
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2780885/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4737556

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