PROTECTION OF XENOGENEIC ENDOTHELIUM IN A PORCINE KIDNEY

University Of Minnesota Twin Cities, Minneapolis MN

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Abstract

Vascular endothelial cells (EC) in a porcine organ that is transplanted into a primate are a major target of injury which, ultimately, results in xenograft rejection. It has been shown that activation of the EC by natural antibodies and complement induce this injury. However, recent in vitro studies have revealed that if this activation with antibodies or the alpha galactosyl-specific lectin Bandeiraea simplicifolia (BS-I) is maintained for a sufficient time, the EC becomes resistant to complement. We hypothesize that the resistance of EC to complement that was induced in vitro can also be induced in the vasculature of a donor organ such that when the organ is transplanted into a recipient primate, the organ is protected from complement-mediated injury. This hypothesis will be tested using a model of pig-to-human xenotransplantation, as the pig is considered to be a potential donor for man. An isolated porcine kidney perfused with whole human blood will be used. This model better represents the situation that may develop when a porcine organ is transplanted into a human, in comparison to a static in vitro model, because injury to EC in a graft occurs under the dynamic influence of blood circulation. The EC of the organ will be activated to resist injury by exposure to BS-I and then subjected to the injurious effects of whole human blood. Our hypothesis will be evaluated with regards to organ survival and function, as well as level of antibody and complement binding to the endothelium, and complement-mediated proinflammatory responses. These studies will provide fundamental knowledge of mechanisms that could be manipulated to protect the vascular endothelium when a solid organ xenograft is transplanted into a human. This may potentially contribute to the success of clinical xenotransplantation to meet the need for organ replacement.