Researchers have made significant progress in xenotransplantation, successfully overcoming a major barrier related to immune rejection in pig kidney transplants. This breakthrough addresses a critical need, as over 800,000 Americans suffer from late-stage kidney disease, yet only 3 percent receive a transplant annually, according to data from the U.S. Centers for Disease Control and Prevention.
To expand the availability of transplantable organs, scientists are investigating genetically modified pig kidneys. These modifications aim to prevent the human immune system from identifying the animal organ as foreign, which typically leads to rejection. Despite these advancements, immune reactions can still cause organ damage and failure post-surgery.
To delve deeper into the mechanisms of xenotransplant rejection, a team led by researchers from NYU Langone Health conducted a pioneering study involving the transplantation of a genetically engineered pig kidney into a brain-dead recipient. The recipient’s family donated his body for research, enabling the team to collect invaluable data over a period of 61 days post-surgery. This extended timeframe allowed for comprehensive sampling of tissue, blood, and body fluids—an opportunity not feasible in living subjects.
Mapping Immune Responses in Transplants
The findings of this study were published in two reports in the journal Nature on November 13, 2023. The first report details a comprehensive mapping of immune activity in both the human recipient and the pig kidney. The researchers identified that rejection was primarily driven by antibodies, which tag foreign substances for destruction, as well as T cells, which are responsible for directly targeting invaders.
The team successfully reversed the rejection process using a combination of FDA-approved drugs that mitigated both antibody and T cell activity. Remarkably, there was no evidence of permanent damage or diminished kidney function after intervention. Dr. Robert Montgomery, the lead author of the study and Professor of Surgery at NYU Grossman School of Medicine, emphasized that this research enhances understanding of how to anticipate and manage harmful immune reactions during pig organ transplantation in living humans.
The second report elaborates on the immune activity observed, with Dr. Montgomery as a co-author. The research team employed a multi-omics analysis, which integrates data on gene function, expression, and proteins. This holistic approach provided a clearer understanding of the complex immune mechanisms at play.
Insights on Immune Reactions and Future Directions
The study evaluated approximately 5,100 expressed human and pig genes within the pig xenograft. It identified various immune cells in the tissue and tracked immune responses over the two-month period, documenting the organ rejection process through daily snapshots.
The analysis revealed three significant immune responses against the pig kidney: on postoperative day (POD) 21, a general response from the human recipient’s immune system; on POD 33, a specific response from macrophages, which engulf invaders; and on POD 45, primarily driven by T cell activity.
Dr. Montgomery noted that the researchers could identify these immune attacks up to five days before they became clinically visible in tissue samples. Co-lead author Dr. Eloi Schmauch from the Keating Lab stated, “Our multi-omics analysis uncovers various biomarkers that show promise as an early-warning system for pig organ rejection.”
Dr. Brendan Keating, the study’s senior author, highlighted that understanding the specific antibodies and T cells responsible for damaging the transplanted pig kidney is crucial for developing targeted therapies. Future research will focus on what molecules the immune response targets through the extensive datasets generated from DNA, RNA, and protein analyses.
Further studies involving living patients are necessary to confirm these findings and advance the field of xenotransplantation. The genetically modified pig organ used in this research was supplied by Revivicor, a subsidiary of United Therapeutics. The studies were funded through several grants from the National Institutes of Health and various foundations.
Dr. Montgomery also holds advisory roles with multiple organizations and companies in the field, ensuring that his affiliations are managed according to the policies of NYU Langone Health.
This landmark research offers hope for addressing the critical shortage of available organs, paving the way for more successful clinical trials in the near future.
