Induction of Tolerance in Murine Autoimmune Diabetes by Transient Blockade of LFA-1/ICAM-1 Pathway

本研究表明，在关键时期短期给予针对白细胞功能相关抗原-1 （LFA-1）和细胞间粘附分子-1 （ICAM-1）的单克隆抗体可完全保护非肥胖糖尿病（NOD）小鼠的自身免疫性糖尿病。当这些单克隆抗体在2周龄时仅给药6天时，在30周龄时未观察到糖尿病或胰岛素。对β细胞Ag(s)的耐受性似乎是由LFA-1/ICAM-1通路的短暂阻断诱导的。保护性抑制活性不足以预防糖尿病，因为在2周龄时接受这些单克隆抗体的雌性NOD小鼠的脾细胞共同转移，只会导致急性糖尿病NOD小鼠的脾细胞过过性转移引起的糖尿病发作的短暂延迟。将这些脾细胞移植到年轻NOD小鼠身上也不能消除自发性糖尿病和胰岛素炎。此外，环磷酰胺处理不能消除保护作用。当将NOD小鼠的脾细胞转移到NOD- scid小鼠身上时，没有一只受体小鼠出现明显的胰岛素炎和随后的显性糖尿病，这表明糖尿病效应T细胞的缺失或失活。然而，接受单抗治疗的无胰岛素NOD小鼠的脾T细胞在体外对胰岛细胞和65-kDa谷氨酸脱羧酶（GAD65）均保持了增殖反应。这些结果表明，在早期NOD小鼠中，LFA-1/ICAM-1通路的短暂阻断诱导了独特的外周耐受性。

The present study demonstrated that a short-term administration of mAbs against leukocyte function-associated antigen-1 (LFA-1) and intercellular adhesion molecule-1 (ICAM-1) at critical periods resulted in complete protection of autoimmune diabetes in non-obese diabetic (NOD) mice. When these mAbs were administered for only 6 days at 2 wk of age, neither diabetes nor insulitis was observed at 30 wk of age. It appears that the tolerance against beta cell Ag(s) was induced by this transient blockade of the LFA-1/ICAM-1 pathway. Protective suppressor activity was not enough to prevent diabetes because co-transfer of splenocytes from female NOD mice, which had received these mAbs at 2wk of age, resulted in only a short delay of the diabetic onset caused by adoptive transfer of splenocytes from acutely diabetic NOD mice. Transfer of these splenocytes to young NOD mice could not also abrogate the spontaneous diabetes and insulitis. Furthermore, cyclophosphamide treatment could not abrogate the protection. 'When splenocytes from the treated NOD mice were transferred to NOD-SCID mice, none of the recipient mice developed significant insulitis and subsequent overt diabetes, suggesting the absence or the inactivation of diabetogenic effector T cells. However, splenic T cells from the insulitis-free NOD mice that had received the mAb treatment preserved proliferative responses to both islet cells and 65-kDa glutamic acid decarboxylase (GAD65) in vitro. These results suggest that a unique peripheral tolerance was induced by the transient blockade of the LFA-1/ICAM-1 pathway in an early age of NOD mice.