Researchers at NYU Langone Health have made significant progress in the field of xenotransplantation, uncovering key mechanisms behind immune rejection of pig kidneys transplanted into humans. This advancement is particularly important given that over 800,000 Americans suffer from late-stage kidney disease, yet only 3 percent receive transplants each year, according to the U.S. Centers for Disease Control and Prevention.
To address the organ shortage, experts have been exploring genetically modified pig kidneys. These modifications aim to prevent the human immune system from recognizing the transplanted organ as foreign, thereby reducing the likelihood of rejection. Despite these advancements, immune reactions can still lead to organ damage after surgery, necessitating further research.
In a groundbreaking study, the NYU Langone team transplanted a genetically engineered pig kidney into a brain-dead donor whose family consented to the use of his body for scientific research. This unique setup allowed for continuous monitoring of the kidney’s interactions with the human immune system over a 61-day period, a process that would be challenging to replicate in living patients or primates.
The findings, published online on November 13, 2023, in the journal Nature, detail a comprehensive mapping of immune activity in both the human and pig kidneys in response to the transplant. The researchers discovered that the rejection was primarily driven by antibodies—immune proteins that identify foreign substances for destruction—and T cells, which specifically target invaders.
Once the immune reactions were identified, the team successfully reversed the rejection using a combination of FDA-approved drugs that inhibited both antibody and T cell activity. Notably, no permanent damage or reduction in kidney function was observed following this intervention.
“Our results better prepare us for anticipating and addressing harmful immune reactions during pig-organ transplantation in living humans,” said Robert Montgomery, MD, PhD, the study’s lead author and chair of the Department of Surgery at NYU Langone Transplant Institute.
The second report in Nature provided a more in-depth analysis of the immune response. This multi-omics study integrated data on gene function, expression, and protein interactions to gain a holistic understanding of the immune mechanisms at play.
By examining approximately 5,100 expressed human and pig genes in the xenograft, researchers identified various types of immune cells and tracked their behavior over the two-month observation period. They noted three significant immune responses against the pig kidney: one on postoperative day (POD) 21, driven by the innate immune system; another on POD 33, led by macrophages; and a third on POD 45, primarily influenced by T cell activity.
Dr. Montgomery emphasized that the study’s findings allow for the early detection of immune attacks through the measurement of specific blood biomarkers. “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.
The implications of this research are vast. The immune responses detailed in the study pinpoint both pig and human targets for potential therapies, which could enhance the success of xenotransplantation efforts.
Moving forward, Dr. Brendan Keating, senior author of the study, indicated that the next step involves investigating the specific molecules targeted by the immune response across the various layers of DNA, RNA, and protein datasets collected. He emphasized the need for further studies involving other human decedents and living patients to validate these findings.
The genetically modified pig organ used in this study was provided by Revivicor, a subsidiary of United Therapeutics. The research received funding from several grants from the National Institutes of Health and various foundations and institutions.
In conclusion, this research not only sheds light on the complex interactions between human immune systems and pig organs but also opens the door to new therapies that could alleviate the critical shortage of available kidneys for transplant.
