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 (hsp7O) had no effect on the development of diabetes.Type 1 or insulin-dependent diabetes mellitus (IDDM) is caused in most cases by autoimmune destruction of the insulin-producing beta cells resident in the islets of the pancreas (1). It is thought that once the autoimmune process takes root, it progresses relentlessly without causing symptoms until the number of beta cells irreversibly destroyed is so large, perhaps 90% of the beta-cell mass, that the individual suffers a derangement in glucose homeostasis and requires an exogenous supply of insulin to sustain life.The non-obese diabetic (NOD/Lt) mouse is a useful experimental model of IDDM (1). NOD/Lt mice spontaneously develop inflammation of the islets, insulitis, beginning at 4-6 weeks of age which progresses to overt IDDM at 4-5 months of age. Autoimmune T lymphocytes would seem to be the cause of beta-cell destruction because IDDM can be adoptively transferred to very young prediabetic NOD/Lt mice with T lymphocytes from older mice (2).Identification of target antigens recognized in the pathogenesis of IDDM is important for at least two reasons: specific antigens would facilitate the early diagnosis of preclinical IDDM and they might be used to abort the destructive autoimmune process through modification of the autoimmune response. For example, copolymer 1 (COP 1), a synthetic peptide immunologically cross-reactive with myelin basic protein has been used to alter the course of multiple sclerosis (3).We now show that a beta-cell antigen cross-reactive with a 65-kDa heat shock protein (hsp65) of Mycobacterium tuberculosis, termed hsp65 cross-reactive (hsp65-CR) antigen, is involved in the pathogenesis of NOD/Lt mouse IDDM.
MATERIALS AND METHODSMice. The breeding nucleus of NOD/Lt mice was a gift of E. Leiter (Jackson Laborat...