Targeting mucosal addressin cellular adhesion molecule (MAdCAM)-1 to noninvasively image experimental Crohn's disease.
OBJECTIVE
Inflammatory bowel disease (IBD) is the second most common chronic inflammatory disorder worldwide; however, a noninvasive means of accurately assessing the severity and extent of intestinal inflammation is currently not available. The aim of the present study was to develop a noninvasive imaging modality to detect and evaluate ileitis in SAMP1/YitFc (SAMP) mice.


METHODS
An image-enhancing ultrasound (US) contrast agent, consisting of encapsulated gaseous microbubbles (MB), was developed specifically to bind mucosal addressin cellular adhesion molecule-1 (MAdCAM-1), a mucosal-restricted addressin up-regulated during gut inflammation. MAdCAM-1-targeted MB (MB(M)) were tested for binding specificity on MAdCAM-1 protein and tumor necrosis factor (TNF)-stimulated SVEC4-10 endothelial cells using an in vitro flow chamber assay and for their ability to detect and quantify ileitis by intravital microscopy and transabdominal US.


RESULTS
Under in vitro flow conditions, a 100-fold increase in MB(M) binding was observed on MAdCAM-1 protein compared with nonspecific MB (P < .001). TNF-stimulated endothelial cells bound significantly more MB(M) vs nonspecific MB (P < .001), which was abrogated after preincubation with anti-MAdCAM-1 antibodies (P < .001). In vivo, MB(M) specifically accumulated in focal areas of ileal inflammation and produced stronger acoustic echoes, measured by average video intensity, in SAMP vs uninflamed AKR mice (P < .001) or SAMP given nonspecific MB (P < .001). MB(M)-specific video intensity showed a strong positive correlation with total ileal inflammatory scores (R2 = 0.92).


CONCLUSIONS
We have developed a novel intravascular US contrast agent targeting MAdCAM-1 that specifically detects and quantifies intestinal inflammation in experimental ileitis, providing the potential for a reliable, noninvasive means to diagnose and monitor disease in patients with IBD.
Bachmann
Christopher
C
Division of Gastroenterology and Hepatology/Digestive Health Center of Excellence, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Klibanov
Alexander L
AL
Olson
Timothy S
TS
Sonnenschein
Jason R
JR
Rivera-Nieves
Jesus
J
Cominelli
Fabio
F
Ley
Klaus F
KF
Lindner
Jonathan R
JR
Pizarro
Theresa T
TT
D000818:Animals; D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D018929:Cell Culture Techniques; D003424:Crohn Disease / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D005434:Flow Cytometry; D007136:Immunoglobulins / Q000032:analysis; D007150:Immunohistochemistry; D007249:Inflammation; D007422:Intestines / Q000276:immunology / Q000473:pathology; D051379:Mice; D045423:Microbubbles; D009088:Mucoproteins / Q000032:analysis; D012680:Sensitivity and Specificity; D014463:Ultrasonography
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; C504265:MADCAM1 protein, human; D009088:Mucoproteins