title: Therapeutic advantage of anti-VAP-1 over anti-α4 integrin antibody in concanavalin a-induced hepatitis.
abstract: Hepatitis induced by concanavalin A (Con A) in mice is well known to be a T-lymphocyte-mediated injury. It has been reported that T helper (Th)1 and Th2 lymphocytes use α4 integrin and vascular adhesion protein (VAP)-1, respectively, to adhere within the hepatic sinusoids. Therefore, we investigated whether inhibition of these molecules ameliorates or worsens the Con A-induced hepatic injury in vivo. Vehicle or antibody to α4 integrin or VAP-1 was intravenously administered 30 minutes before Con A administration. In control mice Con A markedly increased the serum alanine aminotransferase (ALT) level in a dose-dependent manner, and induced a massive infiltration of CD3, particularly interleukin (IL)-4 producing CD4 T cells and liver injury. Both parameters were reduced by anti-VAP-1 antibody despite antibody only blocking the adhesion, not the amine oxidase activity of VAP-1. Both activities of VAP-1 were eliminated in VAP-1-deficient mice and both Con A-induced liver injury and CD4 T-cell infiltration were eradicated. In contrast to anti-VAP-1, anti-α4 integrin antibody reduced interferon-gamma (IFN-γ)-producing CD3 T cells but this worsened Con A hepatitis, suggesting inhibition of a suppressor cell. Con A induced the recruitment of CD49d(+) monocytic myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) into the liver. Anti-α4 integrin dramatically blocked the influx of MDSCs but not Tregs.
  
  
  CONCLUSIONS
  Our findings show that VAP-1 and α4 integrin have opposing effects in Con A-induced hepatic injury, which is associated with blocking the recruitment of CD4 lymphocytes and monocytic MDSCs, respectively. Moreover, these data provide the rationale for a potential therapeutic approach to target adhesion molecules in autoimmune hepatitis.
authors.affiliation: Calvin, Phoebe & Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada; Department of Physiology and Pharmacology, Faculty of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Woo-Yong
authors.initials: WY
authors.lastname: Lee
authors.forename: Marko
authors.initials: M
authors.lastname: Salmi
authors.forename: Margaret M
authors.initials: MM
authors.lastname: Kelly
authors.forename: Sirpa
authors.initials: S
authors.lastname: Jalkanen
authors.forename: Paul
authors.initials: P
authors.lastname: Kubes
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D006631:Amine Oxidase (Copper-Containing) / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology* / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003208:Concanavalin A / Q000009:adverse effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D039441:Integrin alpha4 / Q000276:immunology*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000888:Antibodies, Anti-Idiotypic; D015815:Cell Adhesion Molecules; D003208:Concanavalin A; D039441:Integrin alpha4; D006631:Amine Oxidase (Copper-Containing); C492678:semicarbazide-sensitive amine oxidase-vascular adhesion protein-1, mouse; D000410:Alanine Transaminase