Complement Inhibition in Xenotransplantation-Where Should the Complement Cascade be Inhibited?

Clinical gene-edited pig organ xenotransplantation has recently become a reality, but some problems remain. The transgenic expression of human complement-regulatory proteins in the pig organs is now an accepted means of reducing the impact of complement activation, and immunosuppressive therapy based on CD40/CD154 co-stimulation pathway blockade has proven a largely effective regimen. However, the potential role of complement inhibitors remains uncertain. The complement cascade is complex and consists of several major pathways (e.g., classical, lectin, alternative, terminal) but with several amplification loops and bypasses. It can be inhibited at several different sites, for example, C1, C3, C5, Factor B, and Factor D. We discuss the effect of the various inhibitors currently available and consider their advantages and disadvantages in relation to xenotransplantation. We tentatively suggest that a C3/C3b complement inhibitor may prove optimal, and that complement inhibition may need to be extended for a prolonged period of time.