STANFORD, Calif. — Scientists at the Stanford University School ofMedicine and Lucile Packard Children's Hospital have devised a new wayto decode the immune signals that cause slow, chronic rejection of alltransplanted kidneys. They've created an immune-system "atlas" that willimprove doctors' ability to monitor transplanted organs and shed lighton the mechanisms of gradual, cumulative kidney malfunction aftertransplant.
"The reason chronic injury occurs in transplanted organs is really amystery," said senior study author Minnie Sarwal, MD, PhD, professor ofpediatrics at the School of Medicine and a nephrologist at PackardChildren's Hospital. "Even patients who receive an organ from anidentical twin develop chronic rejection."
The findings will be published online Feb. 23 in the Proceedings of theNational Academy of Sciences.
Before an organ transplant, doctors check for compatibility between thedonor's and recipient's immune systems, Sarwal said. They examine thegenes encoding small proteins, called human leukocyte antigens, thatlabel the exterior of every cell. These proteins are the immune system'smain mechanism for distinguishing "self" from "non-self" tissues. Onlyidentical twins have perfectly matched human leukocyte antigens; forother organ recipients, doctors use a donor with the closest match theycan find. After transplant, an organ recipient receives strong drugsthat reduce the body's ability to crank out antibodies — immune"search-and-destroy" markers — against the donated kidney.
But the fact that chronic organ rejection occurs even between twinssuggests the immune system is doing more than keeping tabs on humanleukocyte antigens.
The Stanford team set out to find what that was. The researchers deviseda first-of-its-kind method to catalog every one of the antibodiesattacking donated kidneys after transplant. They tracked evidence of alltypes of immune system attack by comprehensively comparing antibodylevels in 18 kidney recipients before and after transplant. To do this,they melded two biological sleuthing systems, first comparing allproteins in the subjects' blood to an array of more than 5,000 humanproteins, then running the results from that analysis through a geneticdatabase that showed which blood proteins were antibodies designed toattack the donated kidney.
"This is pretty revolutionary," Sarwal said. "It opens the door to a lotof exciting work to personalize how we monitor these patients." The newfindings will allow inexpensive, noninvasive blood tests that showwhether a donated kidney is infected, undergoing acute rejection oraccruing chronic injuries that could cause long-term malfunction, she said.
"An individual's antibody profile is a new aspect of human physiologythat can now be surveyed in an unbiased way, the same way genes can,"said co-senior author Atul Butte, MD, PhD, assistant professor ofmedical informatics and of pediatrics. "That's very exciting." Butte isalso a member of the Stanford Cancer Center. Unlike genes, the body'santibodies change over time, a factor that could improve theeffectiveness of personalized medicine, Butte said.
The team's raw data on antibody profiles is now publicly available toother scientists through the Gene Expression Omnibus database maintainedby the National Center for Biotechnology Information, a division of theNational Library of Medicine.
In addition to improving patient monitoring, the team's comprehensivelist of anti-kidney antibodies will spur research on the mechanisms ofchronic kidney rejection. For example, the study establishes for thefirst time what part of the kidney causes the largest immune responseafter transplant.
"To our great surprise, the most immunogenic region of the kidney is therenal pelvis," Sarwal said. The renal pelvis is the cavity deep insidethe organ that collects urine and funnels it toward the bladder. Thenext-largest immune responses were observed at the cortex andglomerulus, regions of the kidney with large blood supplies andextensive exposure to the recipient's immune system. The next step inunderstanding chronic organ rejection will be to identify which specificanti-kidney antibodies are the most reliable harbingers of renalmalfunction, Sarwal said.
"If we can correlate these antibodies with clinical events in the organ,we'll have the tools to extend the life of kidney transplants," Sarwalconcluded.