HYPERACUTE REJECTION IN AN EX VIVO MODEL OF RENAL XENOGRAFTING: Role of the Mediator Response and Its Pharmacologic Manipulation by the Specific Platelet-Activating Factor Antagonist WEB 2086BS

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Abstract

The pharmacologic modulation of the platelet-activating factor antagonist WEB 2086BS on the release of metabolites of the arachidonic acid and the cytokine TNFα was investigated in an ex vivo xenograft model of hyperacute rejection. Pig kidneys were perfused for 60 min in a perfusion system with oxygenated heparinized human or autologous porcine blood, respectively. During autologous perfusion, no alterations in the mediator response could be detected, whereas xenogeneic perfusion induced progressive release of mediators. Treatment by the platelet-activating factor antagonist WEB 2086BS resulted in a significantly reduced liberation of the cytokine TNFα and of prostanoids. The histological findings verified that a hyperacute rejection in the xenogeneic perfused organs had occurred, which was mitigated by the treatment with WEB 2086BS. This observation confirms that inflammatory mediators play a decisive role in hyperacute xenogeneic rejection. The results suggest that suppression or manipulation of mediator-specific tissue receptors by receptor-antagonists could be an additional therapeutic mode to control hyperacute rejection in xenogeneic transplantation.

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