Complement activation is a major barrier to xenotransplantation. We report detailed complement monitoring in a 58-year-old man who received a 10 gene-edited porcine heart expressing human complement regulators CD46 and CD55. Despite these transgenes and prophylactic systemic complement inhibition with C1 esterase inhibitor (C1INH), early surveillance biopsy on post-operative day (POD) 13 showed significant histologic evidence of complement deposition with C3d and C4d within capillaries and endothelial activation. In light of these findings, treatment was escalated to terminal complement inhibition using eculizumab. Post-operative complement activity was assessed via immunohistochemistry and dynamic ex vivo serum assays, including a novel bioluminescent modified Ham (bmHam) assay. Following eculizumab initiation, serum sC5b-9 dropped to undetectable levels, and bmHam cytotoxicity decreased significantly, confirming terminal pathway inhibition. Dilutional bmHam assays further demonstrated stronger complement blockade with eculizumab than with C1INH. However, repeat transplant biopsy on POD 30 biopsy showed persistence of anti-C4d+ and anti-C3c+ staining, and increased C5b-9 compared to POD13. This breakthrough was identified by the dilutional bmHam but was not detected by changes in CH50 or sC5b-9. These findings highlight the potential need for early terminal complement inhibition and integrated functional monitoring as critical components of xenotransplant management.
Cole et al. (Fri,) studied this question.