Lewis M, Giraldo A A, Kong Y C
Clin Immunol Immunopathol. 1987 Oct;45(1):92-104. doi: 10.1016/0090-1229(87)90115-2.
The role of circulatory mouse thyroglobulin (MTg) level in activating mechanisms suppressive to induction of experimental autoimmune thyroiditis (EAT) was studied by two regimens to strengthen normal maintenance of self-tolerance in genetically susceptible mice. One was to administer graded doses of exogenous MTg either 7 days apart or daily for 10 days and then challenge the animals with MTg + LPS. The other was to infuse TSH via an osmotic pump for 7 days. The steady TSH infusion for 7 days resulted in an increase in MTg level peaking on Day 3. Such kinetics of MTg concentration in response to TSH coincided with enhanced resistance to EAT induction. After an initial rapid clearance rate of t1/2 of 3 hr, tolerogenic doses of exogenous MTg sustained similar levels for 2-3 days. In contrast, subtolerogenic doses declined to baseline levels in 2 days or less. Clearance can be best explained by a two-compartment model for distribution with an initial alpha phase (t1/2 about 3 hr), followed by a beta phase (t1/2 about 10 hr). We conclude that, for the prevention of EAT induction in the presence of potent adjuvants (CFA or LPS), a threshold, but above baseline, level of either exogenous or endogenous MTg, represented by the beta phase, is required for a critical period (greater than 2-3 days) to activate suppressor mechanisms over and above homeostatic regulation. Whether MTg concentration raised by TSH (TRH) administration activates suppressor T cells as observed after the injection of a tolerogenic dose of MTg remains to be determined.
通过两种方案研究了循环小鼠甲状腺球蛋白（MTg）水平在激活抑制实验性自身免疫性甲状腺炎（EAT）诱导机制中的作用，以加强遗传易感小鼠自身耐受性的正常维持。一种方案是每隔7天或连续10天每天给予不同剂量的外源性MTg，然后用MTg+脂多糖（LPS）攻击动物。另一种方案是通过渗透泵输注促甲状腺激素（TSH）7天。持续7天输注TSH导致MTg水平在第3天达到峰值。MTg浓度对TSH的这种动力学变化与对EAT诱导的抵抗力增强相吻合。外源性MTg的耐受剂量在最初快速清除率（半衰期t1/2为3小时）后，在2 - 3天内维持相似水平。相比之下，亚耐受剂量在2天或更短时间内降至基线水平。清除过程可以用一个两室分布模型最好地解释，即最初的α相（半衰期约3小时），随后是β相（半衰期约10小时）。我们得出结论，为了在存在强效佐剂（完全弗氏佐剂或LPS）的情况下预防EAT诱导，在关键时期（大于2 - 3天），需要一个高于基线的外源性或内源性MTg阈值水平（以β相表示）来激活超过稳态调节的抑制机制。通过给予TSH（促甲状腺激素释放激素）提高的MTg浓度是否如注射耐受剂量的MTg后所观察到的那样激活抑制性T细胞仍有待确定。
