Hesterberg P E, Winsor-Hines D, Briskin M J, Soler-Ferran D, Merrill C, Mackay C R, Newman W, Ringler D J
LeukoSite Inc., Cambridge, Massachusetts, USA.
Gastroenterology. 1996 Nov;111(5):1373-80. doi: 10.1053/gast.1996.v111.pm8898653.
BACKGROUND & AIMS: Integrins play diverse roles in cellular actions and signalling in the immune system. In the context of mucosal immune responses, the integrin alpha 4 beta 7 has received particular attention because of its intimate involvement in lymphocyte recruitment to normal gastrointestinal mucosa and associated lymphoid tissue. The aim of this study was to determine the functional relevance of alpha 4 beta 7 in the pathogenesis of colonic inflammatory disease using the colitic cotton-top tamarin, an animal model of human ulcerative colitis.
Chronically colitic cotton-top tamarins were given either a cross-reactive monoclonal antibody to human alpha 4 beta 7 or an irrelevant control monoclonal antibody. The animals were then evaluated clinically and mucosal biopsy specimens assessed by histological and quantitative morphometric analysis.
A blocking monoclonal antibody to alpha 4 beta 7 integrin ameliorated inflammatory activity and rapidly improved stool consistency when administered to chronically colitic animals. Furthermore, using morphometric analysis of biopsy specimens, antibody therapy reduced the mucosal density of alpha 4 beta 7+ lymphocytes and alpha 4 beta 7 neutrophils and macrophages.
These results suggest that the alpha 4 beta 7 integrin represents a novel, potentially organ-specific therapeutic target for the treatment of inflammatory bowel disease.
整合素在免疫系统的细胞活动和信号传导中发挥多种作用。在黏膜免疫反应的背景下，整合素α4β7因其与淋巴细胞募集至正常胃肠道黏膜及相关淋巴组织密切相关而受到特别关注。本研究的目的是利用棉顶狨猴（一种人类溃疡性结肠炎的动物模型）确定α4β7在结肠炎症性疾病发病机制中的功能相关性。
给慢性结肠炎的棉顶狨猴注射针对人类α4β7的交叉反应性单克隆抗体或无关对照单克隆抗体。然后对动物进行临床评估，并通过组织学和定量形态计量分析对黏膜活检标本进行评估。
给慢性结肠炎动物注射α4β7整合素的阻断性单克隆抗体可改善炎症活动，并迅速改善粪便稠度。此外，通过对活检标本的形态计量分析，抗体治疗降低了α4β7 +淋巴细胞、α4β7中性粒细胞和巨噬细胞的黏膜密度。
这些结果表明，α4β7整合素是治疗炎症性肠病的一个新的、潜在的器官特异性治疗靶点。
