Molecular Signatures Reveal Delayed Pig Organ Rejection

About 13 people in the United States die every day waiting for an organ transplant. Yet, the transplant waiting list keeps growing; every eight minutes, another person is added. Xenotransplantation, the transfer of organs between different species, can be a promising solution.

“Xenotransplantation could provide an unlimited and renewable source of organs,” said Valentin Goutaudiera nephrologist and researcher at the Paris Institute for Transplantation and Organ Regeneration (PITOR).

Over the past few years, the science of xenotransplantation has greatly advanced because scientists managed to prevent hyperacute organ rejection using genetically modified pigs. But Goutaudier and his colleagues recently found that humans still react to pig organs—these responses are just subtler and delayed.

Using molecular approaches such as spatial transcriptomics and imaging, the researchers found signs of inflammation and immune activation in pig-to-human kidney transplant patients, which may be treated using inhibitor drugs. Goutaudier presented these findings at the annual European Society for Organ Transplantation congress on June 30, 2025.

Knockout Pigs Prevent Hyperacute Organ Rejection

Pigs naturally express a sugar called alpha-gal, an antigen to which human antibodies are highly reactive. If not removed, this sugar could cause hyperacute organ rejection. As a result, Goutaudier said, the donated kidney would turn blue, soft, and non-functional, sometimes within seconds.

To overcome this issue, researchers genetically modified pigs so they would lack alpha-gal. In 2021, surgeons successfully transplanted kidneys from alpha-gal knockout pigs to two brain-dead human patients. Transplant surgeon Robert Montgomery at New York University (NYU) led this effort.

Thanks to alpha-gal knockout pigs, hyperacute organ rejection no longer occurs. And while xenotransplantation remains controversial, earlier this year, the US Food and Drug Administration finally approved the first clinical trial for this experimental therapy after decades.

Goutaudier and his colleagues wanted to assess how the transplanted organs fare long term. In xenotransplantation, this translates to weeks and months after the surgery. These follow-up studies may also help clinicians predict issues that could arise and find ways to prevent or treat them.

“We thought that it’s quite impossible that with just some genetic modification, they did not observe any sign of rejection,” Goutaudier said.

Molecular Analyses Could Reveal Subtle, Delayed Signs of Organ Rejection

Goutaudier and his colleagues have long collaborated with Montgomery to study the signs of organ rejection in human-to-human (allo-) transplantation. To do this, they’ve developed a molecular phenotyping workflow that consists of imaging along with transcriptomics analyses, both bulk and spatial. The latter is performed at the tissue, cellular, and subcellular levels. Alexandre Loupya nephrologist at PITOR, leads this work.

“We use our tools to see if there is rejection, then find the mechanism in order to better personalize the treatment of the patients,” Goutaudier said.

So far, Goutaudier and his colleagues have collaborated with surgeons at NYU and the University of Maryland to study three brain-dead and two living xenotransplantation patients; more are ongoing and planned. They found a strong activation of the complement system, a part of the innate immune response, in the weeks and months after xenotransplantation. For this reason, complement inhibitor drugs will likely be beneficial, Goutaudier said.

Another finding, which the researchers had partially reported, was the visible signs of inflammation in the patients’ glomeruli, the networks of small blood vessels that are responsible for filtering waste from the blood.¹ They also found significant enrichment of transcripts that indicate immune activation. These observations support the researchers’ hypothesis that although hyperacute rejection no longer occurs, patients’ immune cells still react to xenotransplanted organs. “We don’t know why, but we see these patterns in patients,” Goutaudier said. “The pathways may be different, so precision medicine can be a powerful tool.”

Goutaudier added that although there’s no clear evidence that adding more genetic manipulations to pigs would improve xenotransplantation outcomes, researchers shouldn’t necessarily halt future efforts to look for further genetic modifications that could benefit patients.

“We have to find the right balance for the different approaches,” he said. “We need all these studies because nobody has the answer yet.”