Spontaneous loss of T-cell tolerance to glutamic acid decarboxylase in murine insulin-dependent diabetes.
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 IDDM. Whereas a number of autoantibodies are associated with IDDM, 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 (Th1) 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.
Kaufman
D L
DL
Department of Psychiatry and Biobehavioral Sciences, University of California at Los Angeles 90024.
Clare-Salzler
M
M
Tian
J
J
Forsthuber
T
T
Ting
G S
GS
Robinson
P
P
Atkinson
M A
MA
Sercarz
E E
EE
Tobin
A J
AJ
Lehmann
P V
PV
D000375:Aging / Q000276:immunology; D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology* / Q000473:pathology; D000939:Epitopes / Q000276:immunology; D005260:Female; D005968:Glutamate Decarboxylase / Q000276:immunology*; D007165:Immunosuppression Therapy; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D001324:Autoantigens; D000939:Epitopes; D005968:Glutamate Decarboxylase