In Vivo Detection of Vascular Adhesion Protein-1 in Experimental Inflammation

Abstract

Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial glycoprotein which mediates leukocyte-endothelial cell interactions. To study the pathogenetic significance of VAP-1 in inflammatory disorders, an in vivo immunodetection method was used to detect the regulation of luminally expressed VAP-1 in experimental skin and joint inflammation in the pig and dog. Moreover, VAP-1 was studied as a potential target to localize inflammation by radioimmunoscintigraphy. Up-regulation of VAP-1 in experimental dermatitis and arthritis could be visualized by specifically targeted immunoscintigraphy. Moreover, the translocation of VAP-1 to the functional position on the endothelial surface was only seen in inflamed tissues. These results suggest that VAP-1 is both an optimal candidate for anti-adhesive therapy and a potential target molecule for imaging inflammation. Leukocyte migration into tissues is vital for efficient defense against insulting pathogens and foreign antigens. Nevertheless, the same phenomenon is also crucial to inappropriate inflammation and tissue destruction in several types of acute and chronic inflammatory and autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, organ transplant rejection, and ischemia-reperfusion injury. Leukocytes enter from the blood circulation into the tissues by passing through the walls of blood vessels. An essential step in this process is binding of leukocytes to the innermost layer of the blood vessel wall, the endothelium, by adhesion molecules. Multiple adhesion molecules on the leukocytes interact concertedly with their counter-receptors on the endothelium during the adhesion and the subsequent transmigration process.1,2 A change in the functional expression of adhesion molecules on the endothelial surface is an early and specific indicator of inflammation. In fact, recent studies suggest that radioactively labeled monoclonal antibodies against specific endothelial adhesion molecules can be used in the diagnosis of inflammation by nuclear imaging methods. 3,4Human vascular adhesion protein-1 (VAP-1), originally defined by 1B2 monoclonal antibody, is a 170-kd endothelial sialoglycoprotein.5 VAP-1 is inflammation inducible and mediates the early phases of interaction between lymphocytes and endothelium. 6 The expression pattern of VAP-1 in normal and inflamed human tissues has been described 7,8 and the role of VAP-1 in human leukocyte adhesion has been shown in vitro. 5,9 However, practically nothing is known about the translocation of VAP-1 from the inside of the cells to the functional position on the cell surface as well as the significance of VAP-1 in leukocyteendothelium interactions in vivo.The anti-human-VAP-1 mAb 1B2 does not recognize VAP-1 of small laboratory animals such as mouse, rat, or rabbit. However, preliminary screening experiments revealed that 1B2 antibody does recognize porcine and canine blood vessels. That encouraged us to study whether the antigens recognized by 1B2 are the porcine and canine homologues o...

Preclinical Evaluation of a Radioiodinated Fully Human Antibody for In Vivo Imaging of Vascular Adhesion Protein-1–Positive Vasculature in Inflammation

“…However, a minor part of the signal is likely caused by the hepatic elimination of the antibody. Previously, Jaakkola et al studied the in vivo behavior of 123 I-labeled chimeric mouse-human anti-VAP-1 antibody in dogs and pigs using SPECT (11). Their results suggest that uptake in liver is VAP-1-specific.…”

“…For imaging, the rabbits were sedated and anesthetized. To induce synovitis, 4 rabbits were intraarticularly injected with phytohemagglutinin (11).…”

Ischemia‐reperfusion injury is attenuated in VAP‐1‐deficient mice and by VAP‐1 inhibitors

“…VAP-1 has been shown to be inflammation inducible [12,26]. However, it remains unknown whether IRI induces VAP-1 enzymatic activity at the site of primary insult and in remote organs.…”

Small-Molecule Inhibitors of Vascular Adhesion Protein-1 Reduce the Accumulation of Myeloid Cells into Tumors and Attenuate Tumor Growth in Mice

“…In endothelial cells, it is most abundant in high endothelial venules but also present in flat endothelial cells. In these cells, it is mainly present in intracellular vesicles, which then translocate the molecule onto the luminal surface upon certain inflammatory stimuli (7). VAP-1 belongs to the family of semicarbazide-sensitive amine oxidases (SSAOs), which catalyze oxidative deamination of primary amines in the reaction R-CH 2 -NH 2 + O 2 + H 2 O → R-CHO + NH 3 + H 2 O 2 .…”