Sugar coating the blood vessels of organs destined for transplant recipients could reduce organ rejection while allowing patients to ditch anti-rejection drugs, suggests new research out of the University of British Columbia.
While still in the proof-of-concept phase, it’s a significant finding because anti-rejection drugs come with serious side effects such as greater susceptibility to infections and a reduction in the effectiveness of vaccines – including COVID-19 vaccines.
The team’s solution, published last month in Nature Biomedical Engineering, involves chemically engineering a polyglycerol-sialic acid conjugate to fortify the organs’ original sugar coating. The natural coating normally suppresses the immune system’s reaction but is damaged during the organ harvesting, preservation and transplantation process.
“The message the sugar coating sends is ‘I’m you, so don’t attack me,” says medicine professor Dr. Jayachandran Kizhakkedathu. He and his team at the Centre for Blood Research and Life Sciences Institute showed their approach substantially reduced rejection of artery and kidney transplants in mice when tested by collaborators at Simon Fraser University and Northwestern University.
The team used a transglutaminase enzyme from guinea pig liver tissue to get the polyglycerol-sialic acid conjugate sugar replacement to coat the transplant organs’ blood vessels. This enzyme forms an irreversible isopeptide bond between amine donors (for example lysine residues) on the cell surface and glutamine-functionalized (Q-tagged) polymers.
“This means the bond is not easily degraded,” says PhD candidate Daniel Luo, who worked with Kizhakkedathu, along with chemistry professor Dr. Stephen Withers, research associate Dr. Lyann Sim and recent chemistry PhD graduate Dr. Erika Siren.
In addition, the transglutaminase enzyme is an ideal candidate because it works quickly and at low temperatures, says Luo. This is important because organs awaiting transplant can only remain outside the body for a few hours and are most often kept in a 4C preservation bath.
Dr. Siren likens the process to giving the organ a camouflage jacket: “We thought, what if we added stuff to the preservation bath that can coat the organ with something that can protect it from immune recognition while it soaks?”
Significantly, the approach ensures that it is only the transplanted organ that sends the message for the body not to mount an immune response. Anti-rejection drugs, on the other hand, suppress the immune system from attacking all things, which is what makes patients more susceptible to infection.
Simon Fraser University’s Dr. Jonathan Choy and Winnie Enns confirmed that a mouse artery, coated in this way and then transplanted showed strong, long-term resistance to inflammation and rejection. Dr. Caigan Du of UBC faculty of medicine’s department of urologic sciences and Dr. Jenny Zhang of Northwestern University got similar results from a kidney transplant between mice. Dr. Megan Levings, professor in UBC faculty of medicine’s department of surgery and investigator at BC Children’s Hospital Research Institute, then firmed up the findings using new-generation immune cells in vitro.
“We were amazed by the ability of this new technology to prevent rejection in our studies,” Dr. Choy, professor of molecular biology and biochemistry at SFU said in a news release. “To be honest, the level of protection was unexpected.”
Dr. Withers, whose expertise is enzymatic reactions that involve a sugar, says he is also encouraged by the team’s results but cautioned that “glycobiology is still in infant stages. More detail on exactly what a sugar coat is doing is needed in order to understand this better.”
The procedure has been tested only in blood vessels and kidneys in mice so far, and clinical trials in humans could still be several years away. However, the team is optimistic it could work equally well on lungs, hearts and other organs.