Elias D, Prigozin H, Polak N, Rapoport M, Lohse A W, Cohen I R
Department of Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Diabetes. 1994 Aug;43(8):992-8. doi: 10.2337/diab.43.8.992.
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.
以适当低剂量施用时，链脲佐菌素（STZ）毒素可引发自身免疫过程，导致胰岛β细胞被破坏。在本研究中，我们检测了小鼠在STZ诱导的自身免疫性糖尿病发生之前及期间的特异性免疫反应。我们现在报告，针对胰岛素的自发自身抗体的出现可作为对低剂量STZ易感性的标志物。C57BL/KsJ品系的易感雄性小鼠表现出此类抗胰岛素抗体，而抗性雌性小鼠则未表现出。施用低剂量的STZ（每天5次，每次30mg/kg）约20 - 30天后诱导短暂性高血糖，血糖暂时缓解，但约2.5个月后继而出现顽固性糖尿病。低剂量STZ引发的致糖尿病过程与携带达纳和米查（DM）独特型的抗胰岛素抗体水平升高有关，随后出现抗独特型抗体，其在糖尿病发作前达到峰值。对热休克蛋白60（hsp60）有反应的抗体和T细胞由低剂量STZ施用引发，并在临床糖尿病出现之前的整个时期持续存在。还观察到对hsp60的p277肽有反应的T细胞。最后，对hsp60进行主动免疫自身可导致短暂性高血糖，并且还会加重低剂量STZ诱导的高血糖。因此，针对胰岛素的自身抗体可表明对糖尿病毒性触发因素的易感性，低剂量毒素可激活先前在非肥胖糖尿病（NOD）品系小鼠的自发自身免疫性糖尿病中检测到的胰岛素和hsp60自身免疫。
