Researchers Overcome Immune Rejection in Pig Kidney Transplants

A significant advancement in xenotransplantation has emerged as researchers at NYU Langone Health have made strides in overcoming immune rejection of pig kidneys transplanted into humans. This breakthrough addresses a critical shortage of available organs, particularly for the more than 800,000 Americans suffering from late-stage kidney disease, of whom only 3 percent receive transplants annually, according to the U.S. Centers for Disease Control and Prevention.

The study, detailed in two reports published online on November 13, 2023 in the journal Nature, involved the transplantation of a genetically engineered pig kidney into a brain-dead recipient. This unique scenario allowed researchers to closely monitor the organ’s interactions with the human immune system over a period of 61 days. Such an extensive observation period is challenging to achieve with live patients or primates.

During this period, the research team collected tissue, blood, and fluid samples, enabling them to map the immune responses triggered by the pig organ. The findings revealed that the rejection of the transplanted kidney was driven primarily by antibodies and T cells, which are integral components of the immune system. The antibodies act by tagging the foreign organ for destruction, while T cells target and eliminate the perceived threat.

Understanding these immune dynamics led to a notable achievement: the successful reversal of rejection episodes using a combination of drugs approved by the Food and Drug Administration. Following this intervention, there was no evidence of permanent damage or impaired kidney function, suggesting a promising pathway for future human applications. As Robert Montgomery, MD, PhD, the study’s lead author and chair of the Department of Surgery at NYU Langone Transplant Institute, stated, “Our results better prepare us for anticipating and addressing harmful immune reactions during pig-organ transplantation in living humans.”

Detailed Immune Activity Analysis

The second report presented a more comprehensive examination of the immune activity related to the pig kidney transplant. Utilizing a technique known as multi-omics analysis, researchers integrated data regarding gene function, expression levels, and protein interactions. This approach allowed them to identify and track every type of immune cell present in the transplant and observe its behavior throughout the monitoring period.

The analysis uncovered three significant immune responses against the pig kidney. On postoperative day 21, an innate immune response emerged, characterized by general reactions to intruders. By postoperative day 33, a specific immune response involving macrophages, a type of white blood cell that engulfs invaders, was observed. The most robust response occurred on postoperative day 45, primarily driven by human T cells.

Dr. Eloi Schmauch, PhD, co-lead author of the study, noted that the researchers were able to detect these immune attacks up to five days before they became clinically visible in the tissue. “Our multi-omics analysis uncovers various biomarkers that show promise as an early-warning system for pig organ rejection,” he explained.

Looking Ahead: Future Research Directions

The implications of this research extend beyond immediate clinical applications. Understanding the specific antibodies and T cells responsible for damaging the transplanted pig kidney opens avenues for targeted therapies. Brendan Keating, PhD, senior author of the study, emphasized that these findings provide clear targets for therapies aimed at improving the success of xenotransplantation.

Future investigations will aim to explore the molecules that the immune response is targeting through the various layers of DNA, RNA, and protein datasets generated during this study. The team plans to conduct additional studies involving other human decedents and eventually live patients to validate their findings and enhance the potential for successful xenotransplantations.

The genetically modified pig organ used in this groundbreaking research was provided by Revivicor, a subsidiary of United Therapeutics. Funding for the studies was sourced from multiple grants from the National Institutes of Health and various foundations, underscoring the collaborative effort behind this significant medical advancement.

As the research community continues to explore xenotransplantation, the potential for addressing the critical organ shortage becomes increasingly tangible. The successful integration of pig organs into human medicine may revolutionize transplant options for patients worldwide, ultimately saving countless lives.