Calcineurin inhibitor-induced endothelial cell injury – A role for complement

Abstract

Calcineurin inhibitor (CNI) use significantly reduced acute rejection rates and revolutionized early allograft and patient outcomes post-transplantation. However, known nephro-and vascular toxicity preclude its use and contribute to chronic allograft injury, negatively impacting longer term outcomes. Evolving evidence suggest a role for complement dysregulation in the pathogenesis of CNI-induced endothelial injury. In an in vitro model using Blood Outgrowth Endothelial Cells (BOEC) isolated from healthy donors and a donor with a pathogenic MCP/CD46 variant, we showed that cyclosporine resulted in a dose and time dependent increase in complement deposition, enhanced by anti-CD59 sensitization. We showed for the first time that MCP/CD46 deficient BOECs were genetically predisposed to be more susceptible to cyclosporine-induced complement deposition (multiple-hit hypothesis). We found complement factor H surface dysregulation to play a key role in cyclosporine-induced complement activation on BOEC surfaces, with glycocalyx abolishment possibly being the key mechanism leading to alternative pathway dysregulation.iii