Lung xenotransplantation: a review.

Abstract

This article reviews recent progress in the field of lung xenotransplantation, including mechanisms of xenograft injury, and the influence of mechanism-directed genetic modifications and other interventions that may soon enable therapeutic use of pig lungs in humans. An extensive series of lung xenotransplantation experiments demonstrates that multiple genetic modifications targeting known xenogeneic lung injury mechanisms are associated with incremental improvements in lung survival or function. Addition of human complement (hCD46, hCD55), coagulation (hEPCR, hTBM, hTFPI, hCD39), or anti-inflammatory pathway regulatory genes (HO-1, HLA-E), and GalT and Neu5Gc gene knockout has each demonstrated protective effects on lung survival or function. In addition, drug treatments targeting key inflammatory and clotting pathways have been shown to attenuate residual mechanisms of lung injury. Work with other pig organs in primate models show that regimens based on costimulatory pathway blocking antibodies prolong xenograft function for months to years, suggesting that once initial lung inflammation mechanisms are fully controlled, clinically useful application of pig lung xenografts may soon be feasible. Genetic modification of pigs coupled with drugs targeting complement activation, coagulation, and inflammation have significantly increased duration of pig lung function in ex-vivo human blood perfusion models, and life-supporting lung xenograft survival in vivo.