Progress in xenotransplantation: overcoming immune barriers

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. This Review summarizes the current state of knowledge regarding immunological barriers to xenotransplantation and discusses the major approaches that are being used to overcome these barriers, including immunosuppression, genetic engineering of pigs and tolerance induction. 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, providin