Antisense therapy of MAdCAM-1 for trinitrobenzenesulfonic acid-induced murine colitis.
BACKGROUND
Anti-alpha4 integrin reagent, natalizumab, which is 1 of the most promising antiadhesion monoclonal antibodies, has been introduced into clinical trials against inflammatory bowel disease (IBD). Lethal consequences such as progressive multifocal leukoencephalopathy have recently been reported in patients using natalizumab, making it critical to determine which selective adhesion molecule in the alpha4 integrins-dependent pathway should be targeted for inhibition and the minimal spectrum of activity required for the valid treatment of IBD. Mucosal addressin cell adhesion molecule (MAdCAM)-1 is known to be restrictedly expressed in gut-associated lymphoid tissues, and its expression dramatically increases in IBD. This study aimed to reevaluate the effectiveness of MAdCAM-1 inhibition and to determine the feasibility of anti-MAdCAM-1 strategy.


METHODS
Antisense MAdCAM-1 oligonucleotides were injected into mice at 1.5 mg/kg/day for 7 consecutive days from the first day of a trinitrobenzene sulfonate enema.


RESULTS
MAdCAM-1 antisense oligonucleotides significantly suppressed the development of trinitrobenzene sulfonate colitis clinically and histopathologically compared with controls. Immunohistochemistry and semiquantitative reverse-transcription polymerase chain reaction of the colon tissues revealed that MAdCAM-1 protein and mRNA expression were lower in antisense-treated mice than in controls. In addition, MAdCAM-1 antisense treatment reduced the number of alpha4beta7 lymphocytes in the inflamed colonic mucosa.


CONCLUSIONS
These data suggest that antisense suppression of MAdCAM-1 is of equivalent effectiveness to that of anti-MAdCAM-1 or anti-alpha4 integrin antibody in previous reports and could be a new therapy for IBD.
Goto
Akira
A
First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo, Japan.
Arimura
Yoshiaki
Y
Shinomura
Yasuhisa
Y
Imai
Kohzoh
K
Hinoda
Yuji
Y
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000378:metabolism / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects*; D005240:Feasibility Studies; D051379:Mice; D008807:Mice, Inbred BALB C; D009088:Mucoproteins; D009841:Oligonucleotides / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D014302:Trinitrobenzenesulfonic Acid; D019282:Wasting Syndrome / Q000139:chemically induced / Q000188:drug therapy
D015815:Cell Adhesion Molecules; C489082:Madcam1 protein, mouse; D009088:Mucoproteins; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014302:Trinitrobenzenesulfonic Acid