Improving Liver Graft Function Using CD47 Blockade in the Setting of Normothermic Machine Perfusion

Background. Toward the goal of using more livers for transplantation, transplant centers are looking to increase the use of organs from "marginal" donors. Livers from these donors, however, have been shown to be more susceptible to preservation and reperfusion injury. Methods. Using a porcine model of donation after circulatory death, we studied the use of antibodymediated CD47 blockade to further improve liver graft function undergoing normothermic machine perfusion. Livers from 20 pigs (5 per group) were brought under either 30 or 60 min of warm ischemia time followed by the administration of CD47 monoclonal antibody (CD47mAb) treatment or immunoglobulin G control antibodies and 6 h of normothermic extracorporeal liver perfusion. Results. After 6 h of normothermic extracorporeal liver perfusion, CD47mAb-treated livers with 30 or 60 min warm ischemia time had significantly lower alanine transaminase levels and higher bile production compared with their respective control groups. Blockade of the CD47 signaling pathway resulted in significantly lower thrombospondin-1 protein levels, lower expression of caspase-3, and higher expression of phosphorylated extracellular signal-regulated kinase. Conclusions. These findings suggested that CD47mAb treatment decreases ischemia/reperfusion injury through CD47/thrombospondin-1 signaling downregulation and the presence of necrosis/apoptosis after reperfusion and could increase liver regeneration during normothermic perfusion of the liver.