Development of a new therapeutic modality with antisense suppression of MAdCAM-1 gene expression for inflammatory bowel diseases

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Background and Aims-Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) is known to be restrictedly expressed in gut associated lymphoid tissues, and its expression level increases in inflammatory bowel diseases (IBD), being a promising target molecule for IBD treatment. This study aims at clarifying the effectiveness of the antisense oligonucleotides specific for murine MAdCAM-1 against trinitrobenzenesulfonic acid (TNBS) -induced colitis. Methods-BALB/c mice were intrarectally received 1 mg of TNBS in 50% ethanol for induction of colitis and administered MAdCAM-1 antisense oligonucleotide, sense, or vehicle alone by s.c. injection. The wasting disease, histologic change, infiltration of CD4 + cell and β7 + cell, and expression of MAdCAM-1 were evaluated. Results-Administration of MAdCAM-1 antisense oligonucleotides significantly suppressed the development of TNBS-induced colitis in the clinical and histopathological aspects, compared to control oligonucleotides. Immunohistochemistry and semi-quantitative RT-PCR of the colon tissues revealed that the expression levels of MAdCAM-1 mRNA and protein were lower in mice treated with the antisense oligonucleotide than in control ones. In addition, the MAdCAM-1 antisense led to a reduction in the number of CD4 + T cells and β7 + cells in the colonic mucosa. Conclusions-The expression of MAdCAM-1 is increased on endothelial cells of the colon from TNBS-induced colitis mice and the suppression of MAdCAM-1 by antisense oligonucleotide significantly prevents the development of TNBS-induced colitis. These data suggest that the antisense suppression of MAdCAM-1 may be a new therapeutic modality for IBD.