Yang X D, Michie S A, Tisch R, Karin N, Steinman L, McDevitt H O
Department of Microbiology and Immunology, Stanford University School of Medicine, Palo Alto, CA 94305-5402.
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12604-8. doi: 10.1073/pnas.91.26.12604.
To elucidate the role of cell adhesion molecules in the pathogenesis of insulin-dependent diabetes mellitus and to determine the predominant lymphocytic homing pathway(s) involved in the selective lymphocytic infiltration of pancreatic islets (insulitis), nonobese diabetic mice were treated with monoclonal antibodies specific for the L-selectin and integrin alpha 4 lymphocyte adhesion molecules. Treatment of neonatal mice with either anti-L-selectin or anti-integrin alpha 4 monoclonal antibodies for the first 4 weeks of life led to a significant and long-term protection against spontaneous occurrence of insulitis and diabetes. The same treatment failed to inhibit lymphocytic infiltration of the salivary glands (sialadenitis). This tissue-specific inhibition of inflammation may be attributed to differences between the pancreas and salivary gland in their expression of endothelial ligands for L-selectin (peripheral vascular addressin) and for integrin alpha 4 (mucosal addressin cell adhesion molecule 1 and vascular cell adhesion molecule 1). Mucosal addressin cell adhesion molecule 1 is highly expressed by vessels within the inflamed islets but was not detected in the salivary glands. In contrast, peripheral vascular addressin- and vascular cell adhesion molecule 1-expressing vessels can be found in almost every area of inflammation within the salivary glands but are seen in only 40-50% of inflamed islets. Anti-L-selectin and anti-integrin alpha 4 treatment had no demonstrable effect on anti-beta-cell autoimmunity or on the immune responses to foreign antigens. Therapeutic treatment with anti-L-selectin after the onset of insulitis from 10 to 14 weeks of age delayed the onset but failed to prevent spontaneous insulin-dependent diabetes mellitus, whereas anti-integrin alpha 4 treatment resulted in a significant and long-lasting suppression of the disease. These data strongly suggest that integrin alpha 4 plays a prominent role in the spontaneous development of insulitis and diabetes in nonobese diabetic mice.
为阐明细胞黏附分子在胰岛素依赖型糖尿病发病机制中的作用，并确定参与胰岛选择性淋巴细胞浸润（胰岛炎）的主要淋巴细胞归巢途径，对非肥胖糖尿病小鼠用针对L-选择素和整合素α4淋巴细胞黏附分子的单克隆抗体进行治疗。在新生小鼠出生后的前4周用抗L-选择素或抗整合素α4单克隆抗体进行治疗，可对胰岛炎和糖尿病的自发发生产生显著且长期的保护作用。同样的治疗未能抑制唾液腺的淋巴细胞浸润（涎腺炎）。这种组织特异性的炎症抑制可能归因于胰腺和唾液腺在L-选择素（外周血管地址素）和整合素α4（黏膜地址素细胞黏附分子1和血管细胞黏附分子1）的内皮配体表达上的差异。黏膜地址素细胞黏附分子1在炎症胰岛内的血管中高度表达，但在唾液腺中未检测到。相反，表达外周血管地址素和血管细胞黏附分子1的血管几乎可见于唾液腺炎症的各个区域，但仅见于40%-50%的炎症胰岛。抗L-选择素和抗整合素α4治疗对抗β细胞自身免疫或对外源抗原的免疫反应没有明显影响。在10至14周龄胰岛炎发作后用抗L-选择素进行治疗可延迟发病，但未能预防自发的胰岛素依赖型糖尿病，而抗整合素α4治疗则导致该疾病得到显著且持久的抑制。这些数据强烈表明，整合素α4在非肥胖糖尿病小鼠胰岛炎和糖尿病的自发发展中起重要作用。
