Tsukamoto K, Yokono K, Amano K, Nagata M, Yagi N, Tominaga Y, Moriyama H, Miki M, Okamoto N, Yoneda R
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
Cell Immunol. 1995 Oct 15;165(2):193-201. doi: 10.1006/cimm.1995.1205.
The interaction of vascular cell adhesion molecule-1 and very late antigen-4 (alpha 4 beta 1-integrin) has been recently known to be profoundly involved in the trafficking of lymphocytes from the circulation into the inflammatory tissues. To elucidate the role of these molecules in the development of autoimmune diabetes, the expression of these adhesion molecules on inflamed islets and the effects of administration of monoclonal antibodies to these molecules on insulitis and overt diabetes were evaluated in nonobese diabetic (NOD) mice. Immunohistochemical study revealed the overexpression of vascular cell adhesion molecule-1 on vascular endothelium near or within inflamed islets and alpha 4-integrin on islet-infiltrating mononuclear cells. Either anti-vascular cell adhesion molecule-1 or anti-alpha 4-integrin monoclonal antibody prevented the transfer of diabetes in irradiated NOD mice which received spleen cells from acutely diabetic NOD mice. When both monoclonal antibodies were administrated to NOD mice during 2-30 weeks of age, neither lymphocytic infiltration to islets nor overt diabetes was observed. Furthermore, administration of these antibodies even from 10 weeks of age could inhibit the development of insulitis and diabetes, whereas administration during 2-5 weeks of age could not. Splenocytes obtained from these treated mice showed no significant change of cytokine production and preserved the ability to transfer diabetes into NOD scid/scid mice. This suggests that treatment with antibodies against these adhesion molecules can inhibit insulitis and diabetes without affecting the Th1/Th2 balance or effector T cells. The blockade of vascular cell adhesion molecule-1/very late antigen-4 interaction would be suitable for therapeutical treatment of the predisposing and latent type I (insulin-dependent) diabetic subjects.
最近已知血管细胞黏附分子-1与极晚期抗原-4（α4β1整合素）的相互作用在淋巴细胞从循环系统转运至炎症组织的过程中发挥着重要作用。为了阐明这些分子在自身免疫性糖尿病发生发展中的作用，我们在非肥胖糖尿病（NOD）小鼠中评估了这些黏附分子在炎症胰岛上的表达以及给予针对这些分子的单克隆抗体对胰岛炎和显性糖尿病的影响。免疫组织化学研究显示，炎症胰岛附近或内部的血管内皮上血管细胞黏附分子-1过表达，胰岛浸润的单核细胞上α4整合素过表达。抗血管细胞黏附分子-1或抗α4整合素单克隆抗体均可阻止接受急性糖尿病NOD小鼠脾细胞的受照射NOD小鼠发生糖尿病转移。在2至30周龄的NOD小鼠中给予这两种单克隆抗体时，未观察到胰岛淋巴细胞浸润或显性糖尿病。此外，即使从10周龄开始给予这些抗体也可抑制胰岛炎和糖尿病的发展，而在2至5周龄时给予则无效。从这些经治疗的小鼠获得的脾细胞细胞因子产生无显著变化，并保留了将糖尿病转移至NOD scid/scid小鼠的能力。这表明用针对这些黏附分子的抗体进行治疗可抑制胰岛炎和糖尿病，而不影响Th1/Th2平衡或效应T细胞。阻断血管细胞黏附分子-1/极晚期抗原-4的相互作用可能适用于对易患和潜伏性I型（胰岛素依赖型）糖尿病患者的治疗。
