• 1.

    Porrett PM, et al. First clinical-grade porcine kidney xenotransplant using a human decedent model. Am J Transplant [published online ahead of print January 20, 2022]. doi: 10.1111/ajt.16930; https://onlinelibrary.wiley.com/doi/10.1111/ajt.16930

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  • 2.

    Kuwaki K, et al. Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: Initial experience. Nat Med 2005; 11:2931. doi: 10.1038/nm1171

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Yamada K, et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of α1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 2005; 11:3234. doi: 10.1038/nm1172

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Chen G, et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys. Nat Med 2005; 11:12951298. doi: 10.1038/nm1330

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Tseng Y-L, et al. α1,3-Galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation 2005; 80:493500. doi: 10.1097/01.tp.0000181397.41143.fa

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Xenotransplantation: No Longer Just the Future of Transplantation?

  • 1 Seth J. Karp, MD, is Director, Transplant Center; Chair, Section of Surgical Sciences; and Surgeon-in-Chief, Vanderbilt University Medical Center, Nashville, TN.
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The old tongue-in-cheek maxim that xenotransplantation is, and always will be, the future of transplantation is under withering attack. Three reports within the past few months—one published in a scientific journal (1) and two in the lay press—suggest xenotransplantation success may be at hand. First, a little history.

Xenotransplantation promises an unlimited supply of organs. Conceptually straightforward, the details turn out to be critically important. First attempts at xenotransplantation using pigs were unsuccessful due to, among other issues, the Galα1,3Gal (Gal) epitope on the vascular epithelium. These epitopes induced refractory rejection, leading to organ loss in transplant models.

The old tongue-in-cheek maxim that xenotransplantation is, and always will be, the future of transplantation is under withering attack. Three reports within the past few months—one published in a scientific journal (1) and two in the lay press—suggest xenotransplantation success may be at hand. First, a little history.

Xenotransplantation promises an unlimited supply of organs. Conceptually straightforward, the details turn out to be critically important. First attempts at xenotransplantation using pigs were unsuccessful due to, among other issues, the Galα1,3Gal (Gal) epitope on the vascular epithelium. These epitopes induced refractory rejection, leading to organ loss in transplant models. Advances in genetic modification technologies allowed this major hurdle to be surmounted in 2005 with four reports that organs from knockout pigs lacking Gal epitopes did not experience acute or hyperacute rejection in primate models (25). Add additional genetic modifications and about 15 years, and the technology has now been brought into humans.

The first publication in a scientific journal reported transplanting pig organs into humans. The study comes from the University of Alabama, where pig kidneys, produced by the company Revivicor, were transplanted into a patient who was declared brain dead (1). Kidney function was not recovered; however, the kidneys did not experience acute or hyperacute rejection, although the vascular lesions were potentially concerning. In a similar scenario, a kidney from a pig was transplanted into a patient with a nonfunctioning brain in New York, and finally and perhaps most excitingly, a pig heart was successfully transplanted into a living human recipient in Maryland and demonstrated function. As of this writing, these last two reports have not been published, and the patient who received the pig heart died a few months after the transplant.

This is incredibly exciting. What happens next? Two major lines of investigation for each type of organ are the following:

  1. Immunologic: What immunologic issues accompany the use of pig organs? What are the optimal immunosuppressive regimens? What is the nature of rejection, and how is it treated? Are these organs subject to chronic rejection, and can this be avoided? What additional genetic modifications could improve immunocompatibility?

  2. Function: Do pig organs faithfully reproduce the function of the corresponding human organ? In particular for the kidneys, will the higher human blood pressure be an issue in the short or long term? Will filtering and other kidney function be appropriate?

Pig organs may have initial difficulty with any of these issues. Even so, the transplant community supports a deep culture of scientific investigation and innovation. Combined with recent major advances in genetic manipulation, it is reasonable to assume that these hurdles will be overcome over time. Concerns about transplantation-mediated zoonoses (e.g., pig viruses) will remain, and these will need to be assiduously monitored. When the recent studies were reported in major media outlets, comment sections were filled with objections to using pigs as organ farms from an animal rights perspective. These concerns will similarly need to be addressed.

The history of transplantation encompasses a series of major breakthroughs, leading to initially limited benefits, followed by continual improvements producing the reliable, outstanding life-saving therapies we have today. The last few months represent one of these major breakthroughs. There is every reason to believe iterations on this achievement will bring xenotransplantation into the mainstream.

References

  • 1.

    Porrett PM, et al. First clinical-grade porcine kidney xenotransplant using a human decedent model. Am J Transplant [published online ahead of print January 20, 2022]. doi: 10.1111/ajt.16930; https://onlinelibrary.wiley.com/doi/10.1111/ajt.16930

    • Search Google Scholar
    • Export Citation
  • 2.

    Kuwaki K, et al. Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: Initial experience. Nat Med 2005; 11:2931. doi: 10.1038/nm1171

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Yamada K, et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of α1,3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 2005; 11:3234. doi: 10.1038/nm1172

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Chen G, et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys. Nat Med 2005; 11:12951298. doi: 10.1038/nm1330

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Tseng Y-L, et al. α1,3-Galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation 2005; 80:493500. doi: 10.1097/01.tp.0000181397.41143.fa

    • Crossref
    • Search Google Scholar
    • Export Citation
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