Korean Circulation Journal

The Korean Society of Cardiology (대한심장학회)
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Historical Review and Future of Cardiac Xenotransplantation

  • Jiwon Koh (Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine) ;
  • Hyun Keun Chee (Department of Thoracic and Cardiovascular Surgery, Konkuk University Medical Center, Konkuk University School of Medicine) ;
  • Kyung-Hee Kim (Division of Cardiology, Incheon Sejong Hospital) ;
  • In-Seok Jeong (Department of Thoracic and Cardiovascular Surgery, Chonnam National University Hospital and Medical School) ;
  • Jung-Sun Kim (Department of Pathology and Translational Genomics, Sungkyunkwan University School of Medicine, Samsung Medical Center) ;
  • Chang-Ha Lee (Department of Thoracic and Cardiovascular Surgery, Bucheon Sejong Hospital) ;
  • Jeong-Wook Seo (Department of Pathology, Incheon Sejong Hospital)
  • Received : 2022.12.09
  • Accepted : 2023.04.05
  • Published : 2023.06.01
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Abstract

Along with the development of immunosuppressive drugs, major advances on xenotransplantation were achieved by understanding the immunobiology of xenograft rejection. Most importantly, three predominant carbohydrate antigens on porcine endothelial cells were key elements provoking hyperacute rejection: α1,3-galactose, SDa blood group antigen, and N-glycolylneuraminic acid. Preformed antibodies binding to the porcine major xenoantigen causes complement activation and endothelial cell activation, leading to xenograft injury and intravascular thrombosis. Recent advances in genetic engineering enabled knock-outs of these major xenoantigens, thus producing xenografts with less hyperacute rejection rates. Another milestone in the history of xenotransplantation was the development of co-stimulation blockaded strategy. Unlike allotransplantation, xenotransplantation requires blockade of CD40-CD40L pathway to prevent T-cell dependent B-cell activation and antibody production. In 2010s, advanced genetic engineering of xenograft by inducing the expression of multiple human transgenes became available. So-called 'multi-gene' xenografts expressing human transgenes such as thrombomodulin and endothelial protein C receptor were introduced, which resulted in the reduction of thrombotic events and improvement of xenograft survival. Still, there are many limitations to clinical translation of cardiac xenotransplantation. Along with technical challenges, zoonotic infection and physiological discordances are major obstacles. Social barriers including healthcare costs also need to be addressed. Although there are several remaining obstacles to overcome, xenotransplantation would surely become the novel option for millions of patients with end-stage heart failure who have limited options to traditional therapeutics.

Keywords

References

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