Researchers at NYU Langone Health have made significant strides in the field of xenotransplantation, addressing a critical challenge that has hindered previous attempts to transplant pig kidneys into humans. This breakthrough comes at a time when more than 800,000 Americans suffer from late-stage kidney disease, of which only 3 percent receive a transplant each year, according to the U.S. Centers for Disease Control and Prevention.
To alleviate the shortage of available organs, scientists are investigating the use of genetically modified pig kidneys. These modifications aim to prevent the human immune system from identifying the animal organ as foreign, which often leads to rejection. Despite these advances, recipients can still experience immune reactions that result in organ damage and failure following transplantation.
In a groundbreaking study, researchers explored the transplantation of a genetically engineered pig kidney into a brain-dead recipient whose family consented to donate his body for research. The recipient’s body was maintained on a ventilator and had a beating heart, allowing the team to collect vital samples over a period of 61 days. This extended timeframe provided an unprecedented opportunity to observe the immune responses involved in both the acceptance and rejection of the pig organ.
The findings, published online on November 13, 2023, in the journal Nature, reveal that rejection of the pig kidney was primarily driven by antibodies and T cells—immune components that target foreign substances for destruction. This comprehensive mapping of immune activity allowed researchers to identify the specific immune responses and, for the first time, successfully reverse rejection using a combination of FDA-approved drugs designed to inhibit both antibody and T cell activity. Notably, there was no evidence of permanent damage or reduced kidney function following the intervention.
Robert Montgomery, MD, PhD, the study’s lead author and the H. Leon Pachter, MD, Professor of Surgery at NYU Grossman School of Medicine, emphasized the implications of the research: “Our results better prepare us for anticipating and addressing harmful immune reactions during pig-organ transplantation in living humans. This sets the stage for more successful clinical trials in the near future.”
The second report in Nature provided a more detailed analysis of immune activity. The research team employed a multi-omics approach, integrating data on gene function, expression, and protein activity to develop a holistic understanding of the complex immune mechanisms at play. By analyzing over 5,100 expressed human and pig genes in the xenograft, researchers were able to identify various immune cell types and track their behavior throughout the two-month period.
The analysis highlighted three significant immune responses against the pig kidney: on postoperative day (POD) 21, triggered by the innate immune system; on POD 33, driven by macrophages—white blood cells that engulf foreign invaders; and on POD 45, predominantly influenced by T cell activity. Montgomery noted that the study revealed biomarkers that could serve as an early-warning system for impending organ rejection, allowing for timely intervention.
“Our multi-omics analysis uncovers various biomarkers that show promise as an early-warning system for pig organ rejection,” stated Eloi Schmauch, PhD, co-lead author from the Department of Surgery’s Keating Lab. The insights gained from this investigation offer clear targets for future therapies aimed at enhancing the success of xenotransplantation, addressing the critical shortage of available organs.
Looking ahead, Brendan Keating, PhD, senior author of the study, indicated plans to investigate the specific molecules targeted by the immune response across the different layers of DNA, RNA, and protein datasets. He emphasized the necessity for further studies involving other human decedents and live patients to validate these findings.
The genetically edited pig organ used in this research was provided by Revivicor, a subsidiary of United Therapeutics. The studies received funding from several grants issued by the National Institutes of Health and other organizations, underscoring the collaborative effort behind this vital research.
As the field of xenotransplantation progresses, the implications of these findings could lead to transformative changes in organ transplantation, potentially saving countless lives and significantly improving the quality of care for patients suffering from kidney disease.
