Ex vivo enzymatic treatment converts blood type A donor lungs into universal blood type lungs
Aizhou Wang, Rafaela Vanin Pinto Ribeiro, Aadil Ali, Edson Brambate, Etienne Abdelnour‐Berchtold, Vinicius Schenk Michaelsen, Yu Zhang, Peter Rahfeld, Haisle Moon, H. Gokhale, Anajara Gazzalle, Prodipto Pal, Mingyao Liu, Thomas K. Waddell, Christine Cserti‐Gazdewich, Kathryn Tinckam, Jayachandran N. Kizhakkedathu, Lori J. West, Shaf Keshavjee, Stephen G. Withers, Marcelo Cypel
Abstract
Donor organ allocation is dependent on ABO matching, restricting the opportunity for some patients to receive a life-saving transplant. The enzymes FpGalNAc deacetylase and FpGalactosaminidase, used in combination, have been described to effectively convert group A (ABO-A) red blood cells (RBCs) to group O (ABO-O). Here, we study the safety and preclinical efficacy of using these enzymes to remove A antigen (A-Ag) from human donor lungs using ex vivo lung perfusion (EVLP). First, the ability of these enzymes to remove A-Ag in organ perfusate solutions was examined on five human ABO-A1 RBC samples and three human aortae after static incubation. The enzymes removed greater than 99 and 90% A-Ag from RBCs and aortae, respectively, at concentrations as low as 1 μg/ml. Eight ABO-A1 human lungs were then treated by EVLP. Baseline analyses of A-Ag in lungs revealed expression predominantly in the endothelial and epithelial cells. EVLP of lungs with enzyme-containing perfusate removed over 97% of endothelial A-Ag within 4 hours. No treatment-related acute lung toxicity was observed. An ABO-incompatible transplant was then simulated with an ex vivo model of antibody-mediated rejection using ABO-O plasma as the surrogate for the recipient circulation using three donor lungs. The treatment of donor lungs minimized antibody binding, complement deposition, and antibody-mediated injury as compared with control lungs. These results show that depletion of donor lung A-Ag can be achieved with EVLP treatment. This strategy has the potential to expand ABO-incompatible lung transplantation and lead to improvements in fairness of organ allocation.