Induction and therapy of autoimmune diabetes in the non-obese diabetic (NOD/Lt) mouse by a 65-kDa heat shock protein.
Insulin-dependent diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells of the pancreas. The results described here indicate that a beta-cell target antigen in non-obese diabetic (NOD/Lt) mice is a molecule cross-reactive with the 65-kDa heat shock protein (hsp65) of Mycobacterium tuberculosis. The onset of beta-cell destruction is associated with the spontaneous development of anti-hsp65 T lymphocytes. Subsequently hsp65 cross-reactive antigen becomes detectable in the sera of the prediabetic mice and some weeks later anti-hsp65 antibodies, anti-insulin antibodies, and anti-idiotypic antibodies to insulin antibodies become detectable. The hsp65-cross-reactive antigen, the autoantibodies, and the T-cell reactivity then decline with the development of overt insulin-dependent diabetes. The importance of hsp65 in the pathogenesis of insulin-dependent diabetes was confirmed by the ability of clones of anti-hsp65 T cells to cause insulitis and hyperglycemia in young NOD/Lt mice. Moreover, hsp65 antigen could be used either to induce diabetes or to vaccinate against diabetes, depending on the form of its administration to prediabetic NOD/Lt mice. Other antigens such as the 70-kDa heat shock protein (hsp70) had no effect on the development of diabetes.
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
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Elias
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Markovits
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Reshef
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van der Zee
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Cohen
D000818:Animals; D001323:Autoantibodies / Q000032:analysis; D001327:Autoimmune Diseases / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D001786:Blood Glucose / Q000378:metabolism; D003001:Cloning, Molecular; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000517:prevention & control / Q000628:therapy; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control / Q000628:therapy; D004926:Escherichia coli / Q000235:genetics; D006360:Heat-Shock Proteins / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D007330:Insulin Antibodies / Q000032:analysis*; D008213:Lymphocyte Activation; D051379:Mice; D008817:Mice, Mutant Strains; D008970:Molecular Weight; D013601:T-Lymphocytes / Q000276:immunology*
D001323:Autoantibodies; D001786:Blood Glucose; D006360:Heat-Shock Proteins; D007330:Insulin Antibodies