Recombinant Human C1-Inhibitor Inhibits Cytotoxicity Induced by Allo- and Xenoantibodies

Abstract

Antibody-mediated rejection (AMR) is usually poorly controlled, especially in the context of pretransplant immunization, and remains an unsolved issue in xenotransplantation. In order to study prevention and/or treatment of AMR through an early blockade of the complement classical pathway, we designed two strategies to test the effect of a new recombinant human C1-inhibitor that inhibits C1 esterase (rhC1-INH; Pharming, The Netherlands), in a complement-dependent cytotoxicity assay, in the contexts of pretransplant anti-donor alloimmunization and pig-to-primate combinations in order to compare the situations. RhC1-INH appeared to be efficient, in allo- and xenotransplantation settings to block cytotoxicity when given at the initiation of (preventive strategy) or during (curative strategy) the cytotoxicity assay. Importantly, we showed that a small amount of exogenous rhC1-INH was sufficient to prevent cytotoxicity induced by anti-donor alloantibody, thus possibly helping to prevent or treat AMR in preimmunized patients. These in vitro data lead to future in vivo studies in models of AMR in pigs and baboons in allotransplantation and xenotransplantation, in which cytotoxicity due to Gal and non-Gal antibodies is so detrimental.