Yagi N, Yokono K, Amano K, Nagata M, Tsukamoto K, Hasegawa Y, Yoneda R, Okamoto N, Moriyama H, Miki M
Second Department of Internal Medicine, Kobe University School of Medicine, Japan.
Diabetes. 1995 Jul;44(7):744-52. doi: 10.2337/diab.44.7.744.
Intercellular adhesion molecule 1 (ICAM-1) plays an important role in the pathogenesis of insulin-dependent diabetes mellitus (IDDM) by being involved in the extravasation of lymphocytes from the circulation into the inflamed pancreas. However, the mechanism of beta-cell destruction by which expression of ICAM-1 on beta-cells may facilitate adhesion of effector cells still remains to be elucidated. Several lines of evidence suggest that this adhesion molecule is involved in the destruction of pancreatic beta-cells by killer lymphocytes in the NOD mouse, which shows an autoimmune diabetic syndrome similar to that of human IDDM. Immunohistochemical study under light microscopy demonstrated that all of the mononuclear cells infiltrating the islets strongly expressed ICAM-1 and leukocyte function-associated antigen 1 (LFA-1), a counterreceptor of ICAM-1, whereas ICAM-1 expression on islet cells was not apparent. However, immunohistochemical staining under electron microscopy revealed that islet beta-cells adjacent to infiltrating lymphocytes were clearly stained by an anti-ICAM-1 monoclonal antibody (mAb). Flow cytometric analysis showed that the ICAM-1 expression on NOD islet cells and NOD-derived insulinoma cells (MIN6N8a) was inducible by interferon (IFN)-gamma or tumor necrosis factor-alpha. These cytokines had an additive effect on the ICAM-1 induction. Susceptibility of MIN6N8a cells to lysis by a NOD islet-derived CD8+ cytotoxic T-cell clone was greatly enhanced by IFN-gamma pretreatment, and this enhancement was abolished by anti-ICAM-1 and anti-LFA-1 mAbs. When both mAbs were administered into NOD mice with spontaneous or adoptively transferred diabetes, the development of diabetes was significantly prevented.(ABSTRACT TRUNCATED AT 250 WORDS)
细胞间黏附分子1（ICAM-1）通过参与淋巴细胞从循环系统外渗进入炎症胰腺，在胰岛素依赖型糖尿病（IDDM）的发病机制中发挥重要作用。然而，β细胞破坏的机制，即β细胞上ICAM-1的表达促进效应细胞黏附的机制仍有待阐明。多项证据表明，这种黏附分子参与了非肥胖糖尿病（NOD）小鼠中杀伤性淋巴细胞对胰腺β细胞的破坏，该小鼠表现出与人类IDDM相似的自身免疫性糖尿病综合征。光学显微镜下的免疫组织化学研究表明，所有浸润胰岛的单核细胞均强烈表达ICAM-1和白细胞功能相关抗原1（LFA-1，ICAM-1的反受体），而胰岛细胞上的ICAM-1表达不明显。然而，电子显微镜下的免疫组织化学染色显示，与浸润淋巴细胞相邻的胰岛β细胞被抗ICAM-1单克隆抗体（mAb）清晰染色。流式细胞术分析表明，NOD胰岛细胞和NOD来源的胰岛素瘤细胞（MIN6N8a）上的ICAM-1表达可被干扰素（IFN）-γ或肿瘤坏死因子-α诱导。这些细胞因子对ICAM-1的诱导具有累加效应。IFN-γ预处理可大大增强MIN6N8a细胞对NOD胰岛来源的CD8 + 细胞毒性T细胞克隆裂解的敏感性，而抗ICAM-1和抗LFA-1 mAb可消除这种增强作用。当将这两种mAb给予患有自发性或过继性转移糖尿病的NOD小鼠时，可显著预防糖尿病的发展。（摘要截短至250字）
