Complement Inhibition Enables Renal Allograft Accommodation and Long-Term Engraftment in Presensitized Nonhuman Primates

Abstract

†S. Chen (Song) and S. Zhong contributed equally to this work.Protection against humoral injury mediated by donorspecific antibodies (DSA), also known as accommodation, may allow for long-term allograft survival in presensitized recipients. In the present study, we determined the role of complement in renal allograft accommodation in donor skin-presensitized nonhuman primates under conventional immunosuppression. Donor skin allografts were transplanted to presensitized recipients 14 days prior to renal transplantation. Renal allografts not receiving any immunosuppressive treatment developed accelerated rejection with predominantly humoral injury, which was not prevented using conventional cyclosporine (CsA) triple therapy. Inhibition of complement activation with the Yunnan-cobra venom factor (Y-CVF) successfully prevented accelerated antibody-mediated rejection and resulted in successful accommodation and long-term renal allograft survival in most presensitized recipients. Accommodation in this model was associated with the prevention of the early antibody responses induced against donor antigens by complement inhibition. Some antiapoptotic proteins and complement regulatory proteins, including Bcl-2, CD59, CD46 and clusterin, were upregulated in the surviving renal allografts. These results suggest that the complement inhibition-based strategy may be valuable alternative in future clinical cross-match positive or ABO-incompatible transplantation.

Complement in disease: a defence system turning offensive

“…In monkeys that had been pre-sensitized with skin grafts, depletion of complement induced long-term survival of a subsequently transplanted kidney 145 . In this model, graft accommodation was associated with upregulation in the expression levels of complement regulatory proteins and anti-apoptotic genes.…”

New milestones ahead in complement-targeted therapy

“…Among the most intriguing aspects of treatment with these complement inhibitors is that in some primate models, a state of accommodation can be achieved within 2–3 weeks of complement inhibition, with sustained prevention of complement attack thereafter [91]; however, neither the conditions for this behavior or its mechanism is fully understood as yet. Meanwhile, in related research, the potential for using complement drugs to enable transplantation across ABO and HLA incompatibility barriers has moved into the spotlight [92], and the development of transgenic pigs expressing human complement regulators (with the αGal epitope removed) has rekindled interest in xenotransplantation [93].…”

Complement in Immune and Inflammatory Disorders: Therapeutic Interventions

“…Though not a classical “inhibitor”, the C3 homolog cobra venom factor (CVF) also targets C3 by forming long-lasting C3 convertases that rapidly deplete C3 stores (32). Therapeutic C3 depletion by CVF and its humanized form (HC3-1496, InCode) has shown efficacy in disease models including AMD (33) and transplantation (34). Of note, HC3-1497 does not act as a C5 convertase (in contrast to some forms of native CVF), thereby alleviating toxicity concerns due to direct generation of massive C5a levels (32).…”