Modulation of fluid-phase complement activation inhibits hyperacute rejection in a porcine-to-human xenograft model.

HYPERACUTE rejection (HAR) of porcine organs is due to classical complement activation by naturally occurring human antibodies to the endothelium. Pigs that are transgenic for human regulators of complement (RCA) seem promising with respect to avoiding HAR, and their use in various studies has brought xenotransplantation closer to clinical reality. However, RCAs are usually expressed on the endothelial cells as clusters and the activation of complement may take place at some distance from RCA localisation. Thus, it should be emphasised that, although RCA pig xenografts may be protected against HAR, a certain degree of complement activation may still contribute to an inflammatory reaction with subsequent impaired graft function. Therefore, efforts should be taken to control the fluid-phase activation of complement, which was the main topic of our studies. We have established an ex vivo perfusion model to investigate the effect of complement manipulation by intravenous immunoglobulin (IVIG), a C3-binding peptide (Compstatin) and C1-inhibitor (C1-INH) on HAR.