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Studies Reveal Cell-by-Cell Changes Caused When Pig Hearts and Kidneys Are Transplanted into Humans

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05/22/2024
nyulangone.org

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.”

Robert Montgomery, MD, DPhil, the H. Leon Pachter, MD, Professor in the Department of Surgery, where he is also chair, was a co-senior author of the kidney paper. The study was co-led by co-senior author Bo Xia, PhD, a graduate student at NYU Grossman School of Medicine at the time of the study who is now a principal investigator at the Broad Institute of MIT and Harvard. Co-first authors were Wanqing Pan and Binghan Zheng, of Dr. Xias group at the Broad Institute, and Weimin Zhang, PhD, of the Institute for Systems Genetics at NYU Grossman School of Medicine. Jiangshan Bai, of the Broad Institute, was another author.

Other NYU Langone study authors were Brendan Camellato, PhD, and Yinan Zhu at the Institute for Systems Genetics; Jeffrey M. Stern, MD, Elaina P. Weldon, ACNP-BC, MSN, Jacqueline Kim, MD, Karen Khalil, PharmD, Massimo Mangiola, PhD, and Adam Griesemer, MD, of the NYU Langone Transplant Institute; Adriana Heguy, PhD, and Peter Meyn in the Genome Technology Center; Ziyan Lin and Alireza Khodadadi-Jamayran of Applied Bioinformatics Laboratories, and Philip M. Sommer, MD, in the Department of Anesthesiology, Perioperative Care, and Pain Medicine.

Along with Dr. Keating, a corresponding author of the Nature Medicine heart study, co-first authors were Eloi Schmauch and Dr. Xia, Brian Piening of the Providence Cancer Institute of Oregon, Maedeh Mohebnasab of the Division of the University of Pittsburgh Medical Center, Chenchen Zhu of Stanford University, Dr. Stern, and Dr. Zhang, of the Institute for Systems Genetics.

Additional authors from the Transplant Institute were Jacqueline Kim, MD; David Andrijevic, MD; Karen Khalil; Ian S. Jaffe; Simon H. Williams, PhD; Elaina P. Weldon; Mercy Williams; Qian Guo; Sophie Widawsky; Vasishta Tatapudi, MD; Massimo Mangiola, PhD; Navneet Narula, MD; Nader Moazami, MD; Harvey I. Pass, MD; and Adam Griesemer, MD. Additional NYU Langone authors were Brendan Camellato, PhD, Larisa Kagermazova, and Yinan Zhu in the Institute for Systems Genetics; Feng-Xia Liang, PhD, and Joseph Sall in the Department of Cell Biology, Adriana Heguy, PhD, in the Department of Pathology, and Han Chen and Ramin Herati, MD, in the Department of Medicine.

Additional authors were from the University of Pennsylvania, Stanford University, University of Oxford, the Broad Institute, Imam Abdulrahman bin Faisal University in Saudi Arabia, the Paris Institute for Transplantation and Organ Regeneration, Cleveland Clinic, University of Eastern Finland, 10x Genomics, United Therapeutics (which provided funding), and Revivicor Inc. All authors are listed in the study manuscript.

The authors would like to thank the families of the decedents for their generous donations to science, and LiveOnNY for providing end-of-life family support. The kidney work was supported through National Institute of Health grants RM1HG009491 and DP5OD033430. The heart work was supported by National Institute of Health grants R01 AI144522 and P30CA016087. Other funding sources of the heart study were the Orion Research Foundation; Yrjö Jahnsson Foundation; the Vilho, Yrjö and Väisälä Fund; the Aarne Koskelon Foundation; and the Antti and Tyyne Soininen Foundation.

Dr. Boeke is a founder and consultant of CDI Labs Inc., Neochromosome Inc., and ReOpen Diagnostics. He serves or has served on the scientific advisory boards of Logomix Inc., Modern Meadow Inc., Rome Therapeutics Inc., Sample6 Inc., Sangamo Inc., Tessera Therapeutics Inc. and the Wyss Institute, all of which are unrelated to the present work.

Dr. Montgomery is on scientific advisory boards for eGenesis, Sanofi, Regeneron, CareDx, and Hansa Biopharma, is a consultant to Recombinetics, and reports consulting fees from Hansa Medical, Regeneron, ThermoFisher Scientific, Genentech, CareDx, One Lambda, ITB Med, Sanofi, and PPD Development, all unrelated to the present work. These relationships are being managed in keeping with the policies of NYU Langone Health.

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Greg Williams
Phone: 212-404-3500
Gregory.Williams@NYULangone.org

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Schedule19 Jun 2024