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Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes

Naturevolume 366pages6972 (1993) | Download Citation

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Abstract

INSULIN-DEPENDENT diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic β-cells and serves as a model for human IDDM1. Whereas a number of autoantibodies are associated with IDDM2, it is unclear when and to what β-cell antigens pathogenic T cells become activated during the disease process. We report here that a T-helper-1 (Thl) response to glutamate decarboxylase develops in NOD mice at the same time as the onset of insulitis. This response is initially limited to a confined region of glutamate decarboxylase, but later spreads intramolecularly to additional determinants. Subsequently, T-cell reactivity arises to other β-cell antigens, consistent with intermolecular diversification of the response. Prevention of the spontaneous anti-glutamate decarboxylase response, by tolerization of glutamate decarboxylase-reactive T cells, blocks the development of T-cell autoimmunity to other β-cell antigens, as well as insulitis and diabetes. Our data suggest that (1) glutamate decarboxylase is a key target antigen in the induction of murine IDDM; (2) autoimmunity to glutamate decarboxylase triggers T-cell responses to other β-cell antigens, and (3) spontaneous autoimmune disease can be prevented by tolerization to the initiating target antigen.

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Author information

Author notes

    • Michael Clare-Salzler

    Present address: Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA

    • Thomas Forsthuber
    •  & Paul V. Lehmann

    Present address: Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio, 44106, USA

Affiliations

  1. Department of Psychiatry and Biobehavioral Sciences

    • Daniel L. Kaufman
    • , Jide Tian
    •  & Grace S. P. Ting
  2. Department of Medicine

    • Michael Clare-Salzler
    •  & Paul Robinson
  3. Department of Microbiology and Molecular Genetics

    • Thomas Forsthuber
    • , Eli E. Sercarz
    •  & Paul V. Lehmann
  4. Department of Biology

    • Allan J. Tobin
  5. Brain Research Institute, and

    • Daniel L. Kaufman
    •  & Allan J. Tobin
  6. Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, 90024, USA

    • Daniel L. Kaufman
    •  & Allan J. Tobin
  7. Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida, 32610, USA

    • Mark A. Atkinson

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https://doi.org/10.1038/366069a0

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