Paik S G, Fleischer N, Shin S I
Proc Natl Acad Sci U S A. 1980 Oct;77(10):6129-33. doi: 10.1073/pnas.77.10.6129.
The role of thymic functions in the development of insulin-dependent diabetes was investigated in athymic nude (nu/nu) mice and euthymic heterozygous (+/nu) littermates of BALB/c origin treated with streptozotocin. The injection of a single high dose of streptozotocin (200 mg/kg body weight) induced rapid and permanent hyperglycemia in both nu/nu and +/nu mice. In contrast, the injection of the same total dose divided into multiple "subdiabetogenic" doses (40 mg/kg per day for 5 consecutive days) caused the development of delayed but progressive hyperglycemia only in the thymus-competent +/nu mice. Female mice of either genotype were significantly less susceptible to streptozotocin at both doses. Restoration of thymic immunity in nu/nu mice by thymus grafts also restored the susceptibility to the hyperglycemic effects of multiple low doses of streptozotocin. Moreover, splenic lymphocytes from +/nu mice previously made diabetic with the multiple low-dose injections of streptozotocin induced transient glucose intolerance in nu/nu mice. The ability of the diabetic spleen cells to transfer the diabetic state was abolished when the splenic lymphocytes were depleted of the T cells but not when they were depleted of B cells. These results provide direct proof that thymus-dependent functions play an obligatory etiologic role in the development of diabetes in mice treated with repeated subdiabetogenic doses of streptozotocin. These observations also add to the growing evidence that autoimmune amplification mechanisms may be critically involved in the etiology of juvenile-onset diabetes mellitus in humans.
在无胸腺裸鼠（nu/nu）以及用链脲佐菌素处理的BALB/c品系有胸腺杂合子（+/nu）同窝小鼠中，研究了胸腺功能在胰岛素依赖型糖尿病发生过程中的作用。注射单次高剂量链脲佐菌素（200mg/kg体重）可使nu/nu和+/nu小鼠均迅速且永久性地出现高血糖。相比之下，将相同总剂量分成多个“亚致糖尿病”剂量（每天40mg/kg，连续5天）注射，仅在有胸腺功能的+/nu小鼠中导致延迟但进行性的高血糖发展。两种基因型的雌性小鼠对两种剂量的链脲佐菌素均明显不敏感。通过胸腺移植恢复nu/nu小鼠的胸腺免疫也恢复了其对多次低剂量链脲佐菌素高血糖作用的易感性。此外，先前经多次低剂量链脲佐菌素注射致糖尿病的+/nu小鼠的脾淋巴细胞可在nu/nu小鼠中诱导短暂的葡萄糖不耐受。当脾淋巴细胞中的T细胞被清除时，糖尿病脾细胞转移糖尿病状态的能力丧失，但B细胞被清除时则不然。这些结果提供了直接证据，表明在经多次亚致糖尿病剂量链脲佐菌素处理的小鼠中，胸腺依赖性功能在糖尿病发生过程中起必然的病因学作用。这些观察结果也进一步证明，自身免疫放大机制可能在人类青少年型糖尿病的病因中起关键作用。
