The ongoing shortage of organs has led researchers to look to alternatives for those in need of transplants. Indeed, only 3% of Americans with late-stage kidney disease receive a transplant each year, according to the U.S. Centers for Disease Control and Prevention (CDC).
To boost the supply of available organs, the use of genetically modified pig kidneys has been explored. One big hurdle is the human immune system, and keeping it from recognizing the animal organ as foreign and attacking it to cause rejection.
To better understand the immune mechanisms behind xenotransplant rejection, a new investigation explored the transplantation of a genetically engineered pig kidney into a brain-dead recipient (decedent) on a ventilator.
For 61 days after the transplant surgery, the team was able to collect samples of tissue, blood, and body fluid at a pace that is impossible to maintain in primates or living patients. They then performed a comprehensive multiomic analysis on the samples to trace the network of interactions that occur among immune cells when a pig organ is being tolerated by a human and when it undergoes rejection.
This work is published in Nature in the paper, “Multi-omics analysis of a pig-to-human decedent kidney xenotransplant.”
The team found that rejection was driven by antibodies as well as by T cells, which target and kill specific invaders. And for the first time, the team successfully reversed the rejection using a combination of drugs approved by the FDA to temper both the antibody and T cell activity. There was no evidence of permanent damage or reduced kidney function after the intervention.
“Our results better prepare us for anticipating and addressing harmful immune reactions during pig-organ transplantation in living humans,” said Robert Montgomery, MD, PhD, professor of surgery at the NYU Grossman School of Medicine. “This sets the stage for more successful clinical trials in the near future.”
The findings also confirmed that a pig kidney can effectively serve as a replacement for a human kidney, said Montgomery.
A second report in Nature outlines the immune activity in greater detail. Measuring about 5,100 expressed human and pig genes in the pig xenograft, the authors identified every type of immune cell in the tissue, tracked immune behavior over the two-month period, and observed the organ rejection in day-by-day snapshots.
The analysis revealed three major immune responses against the pig kidney: on postoperative day 21, driven by the innate immune system, on postoperative day 33, driven by macrophages, and on postoperative day 45, driven mostly by the human T cell response. Montgomery said that by measuring levels of various blood biomarkers, the researchers were able to spot these attacks up to five days before they were clinically visible in the tissue.
“The specific immune reactions revealed in our investigation provide clear pig and human targets for therapies to improve the success of xenotransplantation to address the dire shortage of available organs,” said Brendan Keating, PhD, a faculty member in the Department of Surgery at the NYU Grossman School of Medicine.
According to Keating, now that the researchers understand which antibodies and T cells are damaging the transplanted pig kidney, they plan to investigate what molecules the immune response is targeting through the different layers of DNA, RNA, and protein datasets generated.
