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(American Journal of Pathology. 2004;165:1993-2001.)
© 2004 American Society for Investigative Pathology

Blockade of Vascular Adhesion Protein-1 Inhibits Lymphocyte Infiltration in Rat Liver Allograft Rejection

Timi Martelius^*, Ville Salaspuro^*, Marko Salmi, Leena Krogerus, Krister Höckerstedt^*, Sirpa Jalkanen and Irmeli Lautenschlager^*

From the Departments of Surgery,^* Virology, and Pathology, University of Helsinki and Helsinki University Hospital, Helsinki; and MediCity Research Laboratory, University of Turku, Turku, Finland

Vascular adhesion protein-1 (VAP-1) has been shown to mediate lymphocyte adhesion to endothelia at sites of inflammation, but its functional role in vivo has not been tested in any rodent model. Here we report the effects of VAP-1 blockade on rat liver allograft rejection. BN recipients of PVG liver allografts (known to develop acute rejection by day 7) were treated with 2 mg/kg anti-VAP-1 (a new anti-rat VAP-1 mAb 174–5) or isotype-matched irrelevant antibody (NS1) every other day (n = 6/group) and one group with anti-VAP-1 2 mg/kg daily (n = 7). On day 7, samples were collected for transplant aspiration cytology, histology, and immunohistochemistry. Lymphocyte infiltration to the graft was clearly affected by VAP-blockade. The total inflammation, mainly the number of active lymphoid cells, in transplant aspiration cytology was significantly decreased in animals treated with anti-VAP-1 (4.7 ± 1.0 and 2.4 ± 1.0 corrected increment units, respectively) compared to control (6.6 ± 1.0) (P < 0.05). In histology, the intensity of portal inflammation was significantly decreased (P < 0.05). The amount of T cells expressing activation markers diminished. This is the first demonstration in any prolonged in vivo model that VAP-1 plays an important role in lymphocyte infiltration to sites of inflammation, and, in particular, liver allograft rejection.

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