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

  1. Jide Tian1,
  2. Hoa Dang1,
  3. Harald von Boehmer2,
  4. Elmar Jaeckel3 and
  5. Daniel L. Kaufman1
  1. 1Department of Molecular and Medical Pharmacology, University of California Los Angeles, Los Angeles, California;
  2. 2Laboratory of Lymphocyte Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts;
  3. 3Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
  1. Corresponding author: Daniel L. Kaufman, dkaufman{at}mednet.ucla.edu.

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 DESIGN 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.

Footnotes

  • The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

  • See accompanying commentary, p. 2729..

    • Received June 25, 2008.
    • Accepted September 1, 2009.
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This Article

  1. Diabetes vol. 58 no. 12 2843-2850
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