YSM Issue 95.1

Medicine / Physiology
FEATURE
The pig donor’s red blood cells were
combined with the human recipient’s
serum in a crossmatch for the assay.
This assay tested whether a kidney from
a pig could tolerate an adult human
environment. The negative control was
pooled human male AB serum, while the
positive control serum contained IgG, an
antibody known to react with porcine cells.
In the study, the human recipient’s blood
was mixed with pig cells to demonstrate a
negative crossmatch, allowing
the transplantation to
proceed. This ability to
predict compatibility
between the pig
xenograft and the
human recipient
would prove
to be very
accurate.
The second
hurdle of this
study was
testing for
hyperacute
rejection
without
harming
a living
person.
Hyperacute
rejection
occurs a few
minutes after
the transplant
due to the antigens
being completely unmatched—the body’s
immune system treats the transplanted
organ as a foreign object and attacks it.
The team’s solution was to create the first
human preclinical model.
The Parsons model was named in
honor of Jim Parsons, a fifty-sevenyear-old
man from Huntsville,
Alabama. Parsons had been a
registered organ donor through
Legacy of Hope, which is
Alabama’s organ procurement
organization. In light of
his sense of adventure and
desire to make a difference, the
Parsons family sought to pay tribute to
his character. After Parsons was declared
brain dead and his organs were deemed
unsuitable for donation, the Parsons
family ultimately consented to him
serving as the first preclinical model for
this groundbreaking study.
While human brain death had already
been used to harvest organs for human
transplantation, it was novel to leverage
brain death as a preclinical human
model. One critical concern to be
tested via the model was the vascular
integrity of pig kidneys. Pigs do not
have the same mean arterial pressure
as an adult human being, so whether
the transplanted kidney would be able
to hold its integrity was unknown.
Another goal of this preclinical model
was to determine whether the genetic
engineering, coupled with a negative
prospective crossmatch, were sufficient
to prevent hyperacute rejection.
During surgery, the two pig kidneys
were positioned in the exact anatomic
locations used for human donor kidney
transplantation and employed the same
attachments to the renal artery, renal
vein, and the ureter.
“In the present study, the crossmatch
was performed prior to transplant—
just as happens in human-to-human
transplantation—and it was negative,
predicting there would not be hyperacute
rejection. The only way to validate this
was to perform the actual transplant and
demonstrate the kidney turned pink and
made urine. We did this leveraging the
Parsons Model, and in so doing, answered
key safety questions without risking the
life of a living person,” Locke said.
To the team’s delight, the pig kidneys
reperfused promptly in the same manner
as human transplants. The kidneys retained
optimal color and turgor, the vascular
connections between donor organ and
recipient stayed intact, and there were no
major bleeding episodes. Within around
twenty minutes, the right kidney started
making urine, later followed by the left. The
ureter had successfully carried urine from
the pig kidney into the human bladder.
There was no sign of hyperacute rejection.
This success proved the accuracy of
their crossmatch and firmly established
brain death as a viable preclinical model
IMAGE COURTESY OF TYLER GREER
A Doppler probe is used to assess blood flow inside
the right pig kidney after transplantation into the
human recipient.
for studying the human condition—where
a treatment’s safety and feasibility may be
tested without doing harm to someone.
Such a model would extend far beyond
xenotransplantation—many diseases that
have yet to be understood, along with new
techniques and devices in need of testing
before use on a living person.
In a pathogen-free facility, a herd of
pigs awaits. These pigs will be the proper
size for adult human transplantation by
June 2022. The team hopes that the FDA
will approve their Investigational New
Drug Application and thereby allow the
launch of a phase I clinical trial in living
persons, a process Locke is hopeful to
begin in 2022.
Particularly in the era of COVID-19,
regulatory agencies will rigorously
assess the transmission of viral diseases
from pigs to humans. In this study, the
team tested the pig pre-procurement
to ensure that the pig did not have any
diseases. Further, the human recipient’s
blood was tested post-transplantation
to prove the absence of pig-derived
infections or diseases.
Locke is hopeful that the pig xenograft
kidney will be available for widespread
use as early as five to ten years from now.
She envisions xenotransplantation and
allotransplantation as complementary;
together, there is the real potential to
completely eliminate the waiting list and
wipe out the organ shortage.
For now, our ability to pee may be
secured, one pig at a time. Who knows
what organ or animal will be next. ■
www.yalescientific.org
March 2022 Yale Scientific Magazine 29