Acute vascular rejection is associated with systemic complement activationin a pig-to-primate kidney xenograft model

The introduction of h-DAF transgenic porcine organs into pre-clinical pig-t o-primate discordant xenotransplantation has led to complete and reliable a brogation of hyperacute xenograft rejection (HAR). Despite additional heavy immunosuppression however, most xenografts are still lost due to acute vas cular rejection (AVR), with current treatment protocols being of only limit ed value. In a life-supporting model of pig-to-primate kidney transplantati on, unmodified (n=8) or h-DAF-transgenic (n=9) porcine kidneys were transpl anted into cynomolgus monkeys under cyclophosphamide (CyP), cyclosporine an d low-dose steroid immunosuppression. Longest recipient survival was 11 day s in the control group and 68 days in the h-DAF transgenic group. Stable in itial graft function with recipient survival >4 days was generated in eight animals (two controls and six transgenics). In these animals, plasma compl ement levels were analyzed during ongoing AVR. Compared with baseline level s, a two-fold increase in C3a levels and a four-fold increase in sC5b-9 lev els were measured. In parallel to systemic complement activation, increased deposition of C3 and C5b-9 along with massive staining for recipient IgM i mmunoglobulins was detected in the xenografts on immunohistochemistry. We c onclude that acute vascular xenograft rejection of porcine kidneys in cynom olgus monkeys is associated with classical pathway complement activation fo llowing binding of induced recipient anti-porcine antibodies. This compleme nt activation can be observed despite membrane bound expression of human co mplement regulators in the porcine xenografts. Therefore, additional short- term fluid phase complement inhibition seems necessary for the future devel opment of protocols designed for treatment of AVR in the pig-to-primate com bination.