Lung xenotransplantation: recent progress and current status

Abstract

Xenotransplantation has undergone important progress in controlling initial hyperacute rejection in many pre-clinical models, with some cell, tissue, and organ xenografts advancing toward clinical trials. However, acute injury, driven primarily by innate immune and inflammatory responses, continues to limit results in lung xenograft models. The purpose of this article is to review the current status of lung xenotransplantation – including the seemingly unique challenges posed by this organ – and summarize proven and emerging means of overcoming acute lung xenograft injury.

Platelet sequestration and activation during GalTKO.hCD46 pig lung perfusion by human blood is primarily mediated by GPIb, GPIIb/IIIa, and von Willebrand Factor

“…hCD46, hCD55, hCD59) or coagulation (e.g. hCD39, hTBM, hEPCR) pathway regulatory gene additions have contributed to substantially improved performance of xenogeneic organs in recent years . Particularly for the lung, even with these modifications, activation and sequestration of platelets and leukocytes remain prominent, implicating them in GalTKO.hCD46 lung xenograft injury and failure.…”

Meta‐analysis of the independent and cumulative effects of multiple genetic modifications on pig lung xenograft performance during ex vivo perfusion with human blood

“…Porcine lung xenografts are a promising alternative to critically scarce human allografts if innate immunologic barriers can be overcome . Genetically modified heart, lung, kidney, and islet xenografts have contributed to improved survival in pre‐clinical models .…”

“…Porcine lung xenografts are a promising alternative to critically scarce human allografts if innate immunologic barriers can be overcome . Genetically modified heart, lung, kidney, and islet xenografts have contributed to improved survival in pre‐clinical models . In particular, knocking out the α‐1,3 galactosyl transferase gene (GalTKO) prevents expression of galactose 1,3α‐galactose (Gal) , the primary target of pre‐formed human anti‐pig antibodies .…”

“…Transgenic expression of human proteins responsible for regulating critical complement pathways (hCD46, hCD55, hCD59) has also demonstrated efficacy in various models . Targeting prothrombotic and inflammatory pathways (hTBM, hEPCR, hCD39, HO‐1) and adhesive interactions (HLA‐E) have been proposed to suppress additional mechanisms of xenograft injury, some of which arise from interspecies molecular incompatibilities .…”

Human CD31 on porcine cells suppress xenogeneic neutrophil‐mediated cytotoxicity via the inhibition of NETosis

“…An increasing body of evidence suggests that neutrophils also contribute to CXR . Neutrophils have reported to be activated and induce tissue damage in both xenogeneic antibody‐dependent and antibody‐independent manners .…”