In a groundbreaking series of surgeries at NYU Langone Health, surgical teams successfully performed the world’s first genetically modified pig kidney transplants into human recipients in 2021 and then followed up with the transplantation of two pig hearts in 2022. These procedures were carried out on patients declared dead based on neurologic criteria, with the consent of their families. Subsequently, in April 2024, a pig kidney was successfully transplanted into a living patient, showcasing the advancements in the field of xenotransplantation.
Two new analyses, one published in Nature Medicine and the other in Med, shed light on the changes at the single-cell level in both the organs and the recipient’s bodies before, during, and after the xenotransplantation surgeries. The research teams, consisting of scientists working alongside the surgeons, collected blood and tissue samples to analyze tens of thousands of cells to understand the genetic and cellular activities involved during the transplant procedures.
The findings revealed that, while there was no immediate rejection of the transplanted pig kidneys by the recipients’ bodies, there was a strong immune response in human peripheral blood mononuclear cells (PBMCs). The study identified the onset of “antibody-mediated rejection” at a molecular level, potentially leading to eventual failure of the xenotransplants. Additionally, mechanisms related to tissue repair and cellular growth were observed in the pig kidneys, indicating potential risks that need to be monitored closely.
Through detailed analysis of the interplay between the pig kidneys and the human immune system, researchers found that human immune cells started to dominate signaling within 48 hours post-transplant, affecting the response to the foreign organ. By understanding these cellular mechanisms, researchers hope to improve xenotransplant outcomes by further engineering pig organs or developing tailored immunosuppression treatments for better tolerance of foreign organs.
The second paper published in Nature Medicine focused on a “multiomics” analysis of pig hearts and surrounding human cells in decedents who received heart transplants. The study revealed rapid increases in specific cell types, including activated T cells and natural killer cells within the PBMC group, indicating an intense immune reaction leading to complications such as perioperative cardiac xenograft dysfunction (PCXD). Factors such as recipient heart size and ischemia reperfusion injury were found to influence outcomes in xenotransplant recipients.
The researchers emphasized the importance of utilizing multiomics analysis to understand the broad picture of what occurs in the recipient of a xenograft, helping to identify and potentially counter complications in future procedures. By leveraging these findings, researchers aim to improve the success rates of xenotransplantation and advance the field towards more effective and safe organ transplantation options for patients in need.