Article
Lab Invest 2000, 80:1541–1551
VCAM-1, but Not ICAM-1 or MAdCAM-1, Immunoblockade Ameliorates DSS-Induced Colitis in Mice
This work was supported by grant SAF00-0057 from Comisión Interministerial de Ciencia y Tecnología. Dr. A. Soriano is a recipient of a grant from Comissionat per a Universitats i Recerca de la Generalitat de Catalunya and from Sociedad Andaluza de Patología Digestiva. Dr. M. Sans is a recipient of a grant from SmithKline Beecham-Grupo Español de Trabajo en Enfermedad de Crohn y Colitis Ulcerosa.
Antonio Soriano1, Antonio Salas3, Azucena Salas3, Miquel Sans1, Meritxell Gironella1, Monserrat Elena2, Donald C Anderson4, Josep M Piqué1 and Julián Panés1
- 1Department of Gastroenterology, Institut de Malalties Digestives, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- 2Department of Biochemistry, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
- 3Department of Pathology, Hospital Mutua of Terrassa, Barcelona, Spain
- 4Discovery Research, Pharmacia and Upjohn Laboratories, Kalamazoo, Michigan
Correspondence: Dr. Julián Panés, Gastroenterology Department, Hospital Clínic, Villarroel 170 08036 Barcelona, Spain. Fax: 34 93 451 68 77; E-mail: panes@medicina.ub.es
Received 7 July 2000.
Abstract
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.
