VAP-1-deficient mice display defects in mucosal immunity and antimicrobial responses: implications for antiadhesive applications.
VAP-1, an ecto-enzyme expressed on the surface of endothelial cells, is involved in leukocyte trafficking between the blood and tissues under physiological and pathological conditions. In this study, we used VAP-1-deficient mice to elucidate whether absence of VAP-1 alters the immune system under normal conditions and upon immunization and microbial challenge. We found that VAP-1-deficient mice display age-dependent paucity of lymphocytes, in the Peyer's patches of the gut. IgA concentration in serum was also found to be lower in VAP-1(-/-) animals than in wild-type mice. Although there were slightly less CD11a on B and T cells isolated from VAP-1-deficient mice than on those from wild-type mice, there were no differences in the expression of gut-homing-associated adhesion molecules or chemokine receptors. Because anti-VAP-1 therapies are being developed for clinical use to treat inflammation, we determined the effect of VAP-1 deletion on useful immune responses. Oral immunization with OVA showed defective T and B cell responses in VAP-1-deficient mice. Antimicrobial immune responses against Staphylococcus aureus and coxsackie B4 virus were also affected by the absence of VAP-1. Importantly, when the function of VAP-1 was acutely neutralized using small molecule enzyme inhibitors and anti-VAP-1 Abs rather than by gene deletion, no significant impairment in antimicrobial control was detected. In conclusion, VAP-1-deficient mice have mild deviations in the mucosal immune system and therapeutic targeting of VAP-1 does not appear to cause a generalized increase in the risk of infection.
Koskinen
Kaisa
K
MediCity Research Laboratory, Turku, Finland.
Nevalainen
Suvi
S
Karikoski
Marika
M
Hänninen
Arno
A
Jalkanen
Sirpa
S
Salmi
Marko
M
D006631:Amine Oxidase (Copper-Containing) / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001422:Bacterial Adhesion / Q000276:immunology*; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003384:Coxsackievirus Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018928:Immunity, Mucosal / Q000276:immunology; D007070:Immunoglobulin A / Q000097:blood / Q000276:immunology; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology; D008221:Lymphoid Tissue / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010581:Peyer's Patches / Q000166:cytology / Q000378:metabolism; D016201:Receptors, Lymphocyte Homing / Q000276:immunology; D013209:Staphylococcal Vaccines / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology
D015815:Cell Adhesion Molecules; D007070:Immunoglobulin A; D016201:Receptors, Lymphocyte Homing; D013209:Staphylococcal Vaccines; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse