How Cells React to Pig Heart and Kidney Transplants in Humans

Surgical teams at NYU Langone Health performed the world’s first genetically modified pig kidney transplants into a human body in September and November 2021, and then transplanted two pig hearts in the summer of 2022. These procedures were done in patients declared dead based on neurologic criteria (decedents) and maintained on ventilators with the consent of their families. Demonstrating the field’s progress, NYU Langone in April 2024 transplanted a pig kidney into a living patient.

Now two new analyses, one published May 21 in Med and the other published online on May 17 in Nature Medicine, reveal changes at the single-cell level in the organs and recipients’ bodies before, during, and just after the xenotransplantation surgeries in decedents. Teams of scientists worked alongside the surgeons, taking blood and tissue samples to analyze changes in tens of thousands of collected cells.

Led by researchers at NYU Grossman School of Medicine and the Broad Institute of MIT and Harvard University, the Med paper tracked the genetic and cellular activity in the two pig kidneys transplanted into humans and compared them with pig kidney samples that had not been transplanted. To do so, the research team used several techniques, including single-cell RNA sequencing, which determined the order (sequence) of the molecular letters making up the pig and human genes active in various cell types during the procedures.

The study showed that the transplanted pig kidneys, although not rejected outright by the recipients’ bodies (there was no immediate kidney failure), caused a strong reaction in human peripheral blood mononuclear cells (PBMCs), a set of immune cells that attack transplanted (foreign) organs much like they attack foreign invaders, such as viruses. While immediate rejection was not seen, in part due to treatment with medications that suppress it, the new study found evidence of subtler reactions that could cause xenotransplants to fail over time.

Specifically, the pig kidneys were seen to trigger “antibody-mediated rejection” at the molecular level. As the body develops immune proteins called antibodies specific to a transplanted organ, they recruit natural killer cells, macrophages, and T cells that can injure it. The team also saw an uptick in pig kidneys of tissue repair mechanisms, where certain cells multiply as part of the growth involved in healing. Normal cells that transform into cancer cells also grow aggressively, so the mechanism bears watching.

“We have detailed the cellular mechanisms that dictate how human immune cells react to a xenotransplant in the short term,” said Jef D. Boeke, PhD, a co-senior author on both studies and director of the Institute for Systems Genetics at NYU Grossman School of Medicine. “These results give us new insights into how we might further engineer pig organs for transplant, or tailor immunosuppression treatments to improve tolerance of a foreign organ.”

By tracking the interplay between the kidneys and human system several times a day, the researchers found that pig organ immune cells drove reactions right after the transplant, but that human immune cells infiltrated the pig organs within 48 hours to dominate signaling. Measuring the degree to which pig immune cells trigger the first wave of immune attack on transplants (xenografts) will shape efforts to prevent irreversible cellular damage to them in the future, say the study authors.

Transplanted Hearts

The other new paper, published in Nature Medicine, featured a “multiomics” analysis of pig hearts and surrounding human cells in decedents. This included analyses every six hours after transplant of gene activity (transcriptomics), as well as proteins (proteomics), lipids, and metabolites (intermediates in biological pathways) present in cells. Rapid—and massive—increases in the number of certain cell types were also seen in decedents receiving pig hearts. In D1, one of the human decedents, but not in the other, activated T cell and natural killer (NK) cell populations within the PBMC group increased from about 1 percent 30 hours posttransplant to more than 20 percent of the entire PBMC population 66 hours after the procedure. This dramatic immune reaction to the organ, a complication called perioperative cardiac xenograft dysfunction (PCXD), came with a damaging inrush of immune cells (inflammation) and misplaced healing attempts (tissue remodeling) that thicken tissue and can hinder function.

The worse outcomes experienced by the one decedent may be partly because this heart was smaller than anticipated for the recipient’s size and required an extra procedure to compensate for it, the researchers said. These factors may have cut off blood flow and oxygen to the heart for longer, which is known to cause ischemia reperfusion injury when the supply is restored. The research team observed that PCXD-related immune changes got worse in the presence of reperfusion injury.

“This study demonstrated that multiomics can be used to reveal a broad picture of what is happening in the recipient of a xenograft,” said Brendan Keating, PhD, a co-senior author on both studies and a member of the faculty in the Department of Surgery at NYU Grossman School of Medicine. “The team that did the xenotransplant had several theories about why the first decedent was having more issues, but multiomics helped to define the complications, and may be used to counter them moving forward.”

References: 

1. Pan W, Zhang W, Zheng B, et al. Cellular dynamics in pig-to-human kidney xenotransplantation. Med. 2024;0(0). doi: 10.1016/j.medj.2024.05.003

2. Schmauch E, Piening B, Mohebnasab M, et al. Integrative multi-omics profiling in human decedents receiving pig heart xenografts. Nat Med. 2024;30(5):1448-1460. doi: 10.1038/s41591-024-02972-1

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