Canadian scientists have discovered a cellular structure that may be responsible for previously unexplained organ transplant rejections. Researchers at the University of Montreal Hospital Research Centre turned their attention to blood vessels, which, when damaged, can make rejection difficult to manage.

"We discovered that the damaged blood vessels release specific bits of cells: small membrane vesicles that put the immune system on alert," said Melanie Dieudé, a researcher and the study's first author. "If we then perform a transplant, the immune system immediately attacks the donor organ."

The discovery could change the way physicians assess the risk of rejection in patients who receive heart, lung, kidney or liver transplants.

"We have found the mechanism that makes patients react against components of their own blood vessels even before receiving an organ transplant, and we have identified a drug that can prevent this type of rejection," said Dr. Marie-Josée Hébert, a transplant physician and researcher on the study.

Study findings were published in Science Translational Medicine in December.

Rejection is always a risk with transplants. In most patients, the body's immune system is triggered by the transplant. Human leucocyte antigens are present on all cells and serve as a unique identifier for each person. When a transplant is done, physicians attempt to avoid rejection by making certain the donor and recipient have compatible blood group and HLA antigens. Even with these steps, 10 percent of transplants result in rejection.

That's what makes the discovery of the tiny vesicles so promising. The vesicles are produced by dying cells and produce autoantibodies.

"In addition to the immune system reacting against HLAs, it surprisingly reacts against components of our own cells. So rejection is not simply a reaction against another person, it is also a reaction against elements that belong to us," said Hébert, who co-directs the Canadian National Transplant Research Program.

As a potential treatment, Hébert's team neutralized the enzyme driver of these vesicles using bortezomib, a drug used to treat bone marrow cancers. The bortezomib blocks the enzyme activity of the vesicles, thus making the body's immune system unaware of alerts. Cultured cells and animal models show promising results, and a human clinical trial is currently underway.

"If a recipient has already reacted to these small vesicles and receives an organ that is also in the process of releasing vesicles, it is probably a dangerous situation. This is what we are still examining," Hébert said.

Organ transplants have been conducted since 1954, and the medicine behind transplants has improved drastically in the past 65 years. This latest discovery could help save more lives by changing the way physicians manage the risk of rejection prior to transplantation surgery.

“It is still too early to consider changing clinical guidelines, but I think it could one day change how organs are allocated for transplants," Hébert said. "Organ recipients could also be treated before the operation to make them more silent to these signals coming from ourselves."