NEW
YORK, May 21, 2024 /PRNewswire/ -- 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 online on May 17 in Nature Medicine and the other
May 21 in Med, reveal changes
at the single-cell level in the organs and recipient's bodies
before, during, and just after the xenotransplantation surgeries in
the decedents. Teams of scientists had 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, the Med paper tracked the genetic
and cellular activity in the two pig kidneys transplanted into
humans, and compared them against pig kidney samples that had not
been translated. 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, while not
rejected outright by the recipients' bodies (no immediate kidney
failure), caused a strong reaction in human peripheral blood
mononuclear cells (PBMCs). This set of immune cells can attack
transplanted (foreign) organs much like they attack foreign
invaders, such a viruses. While immediate rejection was not seen,
in part due to treatment with medications that suppressed 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 Boeke, PhD, a co-senior author
on both studies, and director of the Institute for System 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 each day, the researchers found that pig kidney
immune cells drove reactions right after the transplant, but that
human immune cells infiltrated the pig organs by 48 hours to
dominate signaling. Measuring the degree to which pig immune cells
trigger the first wave of immune attack on xenotransplants will
shape efforts to prevent irreversible cellular damage to them, 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 of
proteins (proteomics), lipids, and metabolites (intermediates in
biological pathways) present in cells.
Rapid, massive increases in the number of certain cell types
were also seen in decedents receiving pig hearts. In one of the
decedents (designated D1) but not the other, activated T cell and
natural killer (NK) cell populations within the PBMC group
increased from about one percent 30 hours post-transplant to more
than 20 percent of the entire PBMC population by 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 the
oxygen supply 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 reactions to the
pig organ got worse in the presence of this recipient's 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 faculty in 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 chair of
the Department of Surgery at NYU Langone Health was a
co-senior author of the kidney paper. This study was also led by
co-senior study author Bo Xia, PhD,
a graduate student at the time of the study at NYU Grossman School
of Medicine, 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. Xia's group
at the Broad Institute, and Weimin
Zhang of the Institute for Systems Genetics (ISG) at NYU
Grossman School of Medicine. Also a Broad Institute author was
Jiangshan Bai. Other NYU Langone study authors were Brendan Camellato and Yinan Zhu at ISG; Jeffrey Stern, Elaina
Weldon, Jacqueline Kim,
Karen Khalil, Massimo Mangiola, and Adam Griesemer in the NYU Langone Transplant
Institute; Adriana Heguy and
Peter Meyn in the Genome Technology
Center; Ziyan Lin and Alireza
Khodadadi-Jamayran of the Applied Bioinformatics Laboratories, and
Philip Sommer in the Department of
Anesthesiology, Perioperative Care & 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 Center in Portland, Maedeh Mohebnasab of the
Division of the University of
Pittsburgh Medical Center, Chenchen Zhu of
Stanford University, Dr. Stern, and Weimin Zhang, of the
ISG. Also NYU Langone authors were Jacqueline Kim, David
Andrijevic, Karen Khalil,
Ian Jaffe, Simon Williams, Elaina
Weldon, Mercy Williams,
Qian Guo, Sophie Widawsky, Vasishta Tatapudi, Massimo
Mangiola, Navneet Narula,
Nader Moazami, Harvey Pass, Adam
Griesemer in the Transplant Institute; Brendan Camellato, Larisa Kagermazova, and
Yinan Zhu in the ISG; Feng-Xia Liang, and Joseph Sall in Department of Cell Biology,
Adriana Heguy in the Department of
Pathology, and Han Chen and Ramin
Herati in the Department of Medicine.
Additional authors were from the University
of Pennsylvania, Stanford
University, University of
Oxford, 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 donation to science, and LiveOnNY for providing
end-of-life family support. The kidney work was supported in
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; 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 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 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.
Contact: Gregory Williams,
gregory.williams@nyulangone.org
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