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  • Review Article
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Progress in xenotransplantation: overcoming immune barriers

Nature Reviews Nephrology volume 18, pages 745–761 (2022)Cite this article

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Abstract

A major limitation of organ allotransplantation is the insufficient supply of donor organs. Consequently, thousands of patients die every year while waiting for a transplant. Progress in xenotransplantation that has permitted pig organ graft survivals of years in non-human primates has led to renewed excitement about the potential of this approach to alleviate the organ shortage. In 2022, the first pig-to-human heart transplant was performed on a compassionate use basis, and xenotransplantation experiments using pig kidneys in deceased human recipients provided encouraging data. Many advances in xenotransplantation have resulted from improvements in the ability to genetically modify pigs using CRISPR–Cas9 and other methodologies. Gene editing has the capacity to generate pig organs that more closely resemble those of humans and are hence more physiologically compatible and less prone to rejection. Despite such modifications, immune responses to xenografts remain powerful and multi-faceted, involving innate immune components that do not attack allografts. Thus, the induction of innate and adaptive immune tolerance to prevent rejection while preserving the capacity of the immune system to protect the recipient and the graft from infection is desirable to enable clinical xenotransplantation.

Key points

  • As the demand for human organs for transplantation far exceeds the supply, many patients die while waiting for a transplant; xenotransplantation provides a potential near-term solution to the organ shortage.

  • Advances in genetic engineering, immunosuppression and tolerance approaches have contributed to improved pig organ survival in non-human primates (NHPs).

  • Functioning pig islet and heart grafts have survived in NHPs for months and functioning pig kidney grafts have survived in NHPs for years.

  • In 2022, a pig heart was transplanted into a patient with heart failure and functioned for 7 weeks and xenotransplantation experiments using pig kidneys in deceased human recipients provided encouraging data.

  • Mixed haematopoietic chimerism and thymic transplantation approaches have been successfully used to tolerize human T cells, B cells and natural killer cells in human immune system mice, providing proof of their potential to induce immune tolerance.

  • Advances in applying tolerance approaches in NHPs, including genetic engineering of source pigs, support their potential to provide a long-term solution to the powerful immune barriers to xenotransplantation.

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Fig. 1: The growing organ shortage.
Fig. 2: Tolerance induction strategies.
Fig. 3: Tolerance and immune function with transplantation of swine (or hybrid) thymus and mixed xenogeneic chimerism.
Fig. 4: Breeding for multiple transgenes in inbred miniature swine.

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Authors and Affiliations

  1. Columbia Center for Translational Immunology, Department of Medicine, Columbia University, New York, NY, USA

    Megan Sykes & David H. Sachs

  2. Department of Surgery, Columbia University, New York, NY, USA

    Megan Sykes & David H. Sachs

  3. Department of Microbiology and Immunology, Columbia University, New York, NY, USA

    Megan Sykes

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  1. Megan Sykes
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The authors contributed equally to all aspects of the article.

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The authors receive sponsored research support from Choironex, a fully-owned subsidiary of Nephro Health.

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Sykes, M., Sachs, D.H. Progress in xenotransplantation: overcoming immune barriers. Nat Rev Nephrol 18, 745–761 (2022). https://doi.org/10.1038/s41581-022-00624-6

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