Autoimmune diabetes induced by the beta-cell toxin STZ. Immunity to the 60-kDa heat shock protein and to insulin.
Administered at a suitably low dose, the toxin streptozotocin (STZ) can trigger an autoimmune process leading to destruction of the beta-cells of the pancreatic islets. In this study, we examined specific immunological reactions in mice before and during the development of STZ-induced autoimmune diabetes. We now report that the development of spontaneous autoantibodies to insulin can serve as a marker of susceptibility to a low dose of STZ. Susceptible male mice of the C57BL/KsJ strain manifested such anti-insulin antibodies, and resistant female mice did not. Administration of a low dose of STZ (five daily doses each of 30 mg/kg) induced transient hyperglycemia approximately 20-30 days later, which temporarily remitted but was followed by intractable diabetes approximately 2.5 months later. The diabetogenic process triggered by the low dose of STZ was associated with an increase in the level of anti-insulin antibodies bearing the Dana and Micha (DM) idiotype, later followed by the appearance of anti-idiotypic antibodies that peaked before the onset of diabetes. Antibodies and T-cells reactive to hsp60 (heat shock protein) were triggered by the low-dose STZ administration and persisted throughout the period that preceded clinical diabetes. T-cells reactive to the p277 peptide of hsp60 were also observed. Finally, active immunization to hsp60 caused transient hyperglycemia by itself and also aggravated the hyperglycemia induced by low-dose STZ. Thus, autoantibodies to insulin can indicate susceptibility to a toxic trigger of diabetes, and a low dose of a toxin can activate the insulin and hsp60 autoimmunity that has been detected previously in the spontaneous autoimmune diabetes of NOD strain mice.
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
D
D
Elias
H
H
Prigozin
N
N
Polak
M
M
Rapoport
A W
AW
Lohse
I R
IR
Cohen
D000818:Animals; D001323:Autoantibodies / Q000097:blood; D001327:Autoimmune Diseases / Q000139:chemically induced*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000276:immunology*; D005260:Female; D006360:Heat-Shock Proteins / Q000276:immunology*; D007114:Immunization; D007328:Insulin / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013311:Streptozocin / Q000008:administration & dosage
D001323:Autoantibodies; D001786:Blood Glucose; D006360:Heat-Shock Proteins; D007328:Insulin; D013311:Streptozocin