Soriano A, Salas A, Salas A, Sans M, Gironella M, Elena M, Anderson D C, Piqué J M, Panés J
Department of Gastroenterology, Institut de Malalties Digestives, University of Barcelona, Spain.
Lab Invest. 2000 Oct;80(10):1541-51. doi: 10.1038/labinvest.3780164.
Adhesion molecule immunoneutralization is envisioned as a promising therapy for inflammatory bowel disease, but the relative value of selective blockade of different adhesion molecules has not been established. The aims of this study were to measure expression and functional relevance of endothelial intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in leukocyte recruitment in experimental colitis and to compare the therapeutic effectiveness of their selective blockade. For this purpose, cell adhesion molecule expression was measured by the dual radiolabeled antibody technique in mice with dextran sulfate sodium-induced colitis and controls. Leukocyte-endothelial cell interactions were determined in colonic venules by fluorescence intravital microscopy. Therapeutic effects of chronic treatment with anti-ICAM-1, anti-VCAM-1, or anti-MAdCAM-1 antibodies were also assessed. Whereas colonic endothelial ICAM-1 was constitutively expressed and had a mild up-regulation in colitic animals, constitutive expression of VCAM-1 and MAdCAM-1 was low, but markedly increased after induction of colitis. Leukocyte adhesion was abrogated by immunoneutralization of VCAM-1 or MAdCAM-1 but not by treatment with an anti-ICAM-1 antibody. Chronic administration of anti-VCAM-1 antibody, but not anti-ICAM-1 or anti-MAdCAM-1, resulted in significant attenuation of colitis in terms of disease activity index, colon length, ratio of colon weight to length, and myeloperoxidase activity. In conclusion, VCAM-1 plays a central role in leukocyte recruitment in colitis and blockade of this adhesion molecule has higher therapeutic effect than immunoneutralization of ICAM-1 or MAdCAM-1 in this experimental model.
黏附分子免疫中和被视为治疗炎症性肠病的一种有前景的疗法，但不同黏附分子选择性阻断的相对价值尚未确定。本研究的目的是测量实验性结肠炎中内皮细胞间黏附分子1（ICAM-1）、血管细胞黏附分子1（VCAM-1）和黏膜地址素细胞黏附分子1（MAdCAM-1）在白细胞募集中的表达及功能相关性，并比较它们选择性阻断的治疗效果。为此，采用双放射性标记抗体技术在硫酸葡聚糖钠诱导的结肠炎小鼠和对照组中测量细胞黏附分子的表达。通过荧光活体显微镜在结肠小静脉中测定白细胞与内皮细胞的相互作用。还评估了抗ICAM-1、抗VCAM-1或抗MAdCAM-1抗体长期治疗的效果。虽然结肠内皮ICAM-1组成性表达且在结肠炎动物中有轻度上调，但VCAM-1和MAdCAM-1的组成性表达较低，但在结肠炎诱导后显著增加。VCAM-1或MAdCAM-1的免疫中和可消除白细胞黏附，但抗ICAM-1抗体治疗则不能。长期给予抗VCAM-1抗体，而非抗ICAM-1或抗MAdCAM-1抗体，在疾病活动指数、结肠长度、结肠重量与长度之比以及髓过氧化物酶活性方面可显著减轻结肠炎。总之，在该实验模型中，VCAM-1在结肠炎白细胞募集中起核心作用，阻断该黏附分子的治疗效果高于ICAM-1或MAdCAM-1的免疫中和。
