Mechanisms of hyperacute rejection of discordant liver xenograft

: Use of discordant liver xenografts is a possible means of overcoming the ever-increasing organ shortage. Immunological barriers, however, remain the major obstacle to the application of this therapeutic option. The aim of the study was to establish the model and to further investigate mechanisms of hitherto assumed liver xenograft rejection in the discordant guinea pig to rat combination and to determine the role of complement activation in this model. Male guinea pigs served as donors, and all recipient Lewis rats underwent splenectomy prior to orthotopic liver transplantation with a modified cuff technique. Animals were grouped according to their pharmacologic therapy: group 1: control group, no further therapy; group 2: plasmapheresis immediately prior to transplantation; group 3: Cobra venom factor; group 4: plasmapheresis and Cobra venom factor; group 5: Cyclosporin A; and group 6: RS 61443 with three animals in each group. Median survival was 62 (52–68) minutes in group 1, 150 (129–190) in group 2, 745 (260–1034) in group 3, 45 (18–60) in group 4, 91 (76–118) in group 5, and 212 (170–245) in group 6. Histologically, portal and sinusoidal congestion, interstitial haemorrhages, intragraft granulocyte deposits, and parenchymal damage were found to be most pronounced in groups 1 and 3. In all groups endothelial cells stained positive for IgM and complement component C3 compatible with classical pathway activation. From our findings where deposition of Factor H was noted it is concluded that in this discordant model the complement system is activated by the alternative pathway. Intragraft IgM deposits, however, suggest that the classical activation pathway may also be involved.