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Letters to Nature

Nature 366, 69-72 (4 November 1993) | doi:10.1038/366069a0; Accepted 22 September 1993

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

Daniel L. Kaufman*†‡, Michael Clare-Salzler§parallel, Jide Tian*, Thomas Forsthuberparallel, Grace S. P. Ting*, Paul Robinson§, Mark A. Atkinson£, Eli E. Sercarz, Allan J. Tobin†‡** & Paul V. Lehmannparallel

  1. * Department of Psychiatry and Biobehavioral Sciences
  2. § Department of Medicine
  3. Department of Microbiology and Molecular Genetics
  4. ** Department of Biology
  5. † Brain Research Institute, and
  6. ‡ Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California 90024, USA
  7. £ Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA
  8. parallel Present addresses: Department of Pathology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, Florida 32610, USA (M.C.-S.); and Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA (T.F. and P.V.L).
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INSULIN-DEPENDENT diabetes mellitus (IDDM) in non-obese diabetic (NOD) mice results from the T-lymphocyte-mediated destruction of the insulin-producing pancreatic beta-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 beta-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 beta-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 beta-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 beta-cell antigens, and (3) spontaneous autoimmune disease can be prevented by tolerization to the initiating target antigen.