Amelioration of chronic and spontaneous intestinal inflammation with an antisense oligonucleotide (ISIS 9125) to intracellular adhesion molecule-1 in the HLA-B27/beta2 microglobulin transgenic rat model.
Adhesion molecules are known to be an important part of leukocyte migration and extravasation in both homeostatic and inflammatory conditions. Intracellular adhesion molecule-1 (ICAM-1 or CD54) is constitutively expressed on endothelial cells and is up-regulated during acute and chronic inflammation. We investigated the efficacy and consequences of interfering with CD54 after administration of an antisense oligonucleotide to ICAM-1 (CD54) in the transgenic HLA-B27/beta2 microglobulin rat model. One hundred percent of the HLA-B27 transgene + animals will spontaneously develop chronic inflammation (some more severely than others) in the gastric mucosa, cecum, and colon. We carried out two studies, i.p. injection and rectal administration of antisense. Following i.p. and rectal treatment, there were significant decreases in colonic mucosal wall thickness, histologic inflammation, CD54 expression in the colon and peripheral blood, and the percentage of colon weight per end body weight. Furthermore, decreased expression of CD49d, CD18, and tumor necrosis factor-alpha was observed in antisense treated rats. Therefore, the HLA-B27 transgenic model of spontaneous and chronic inflammatory bowel disease, which has increased expression of adhesion molecules, responds to both routes of administration of ICAM-1 antisense oligonucleotides. These studies support the regulatory role of adhesion molecules in chronic intestinal inflammation, the need for an understanding of how the route of drug delivery can alter the dose and area affected, and finally the role of antisense oligonucleotides as a therapeutic modality in chronic spontaneous inflammatory bowel diseases.
Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, AB, Canada. bruce.yacyshyn@med.va.gov
Mary Beth
MB
Bowen-Yacyshyn
C F
CF
Bennett
N
N
Nation
D
D
Rayner
B R
BR
Yacyshyn
D000285:Administration, Rectal; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004751:Enteritis / Q000188:drug therapy*; D005260:Female; D015796:HLA-B27 Antigen / Q000235:genetics*; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics* / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020320:Oligoribonucleotides, Antisense / Q000627:therapeutic use*; D009929:Organ Size / Q000187:drug effects; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011916:Rats, Inbred F344; D020133:Reverse Transcriptase Polymerase Chain Reaction; D001613:beta 2-Microglobulin / Q000235:genetics*
D015815:Cell Adhesion Molecules; D016207:Cytokines; D015796:HLA-B27 Antigen; C442330:ISIS 9125; D020320:Oligoribonucleotides, Antisense; D054735:Phosphorothioate Oligonucleotides; D012333:RNA, Messenger; D001613:beta 2-Microglobulin; D018799:Intercellular Adhesion Molecule-1