Is Chronic Organ Transplant Rejection Due to Bad Lymph Drainage?

When a donor organ is given to a recipient, it’s crucial that the recipient’s immune system doesn’t attack the donated organ as a foreign invader. While organ transplantation has advanced tremendously, there are still major problems with organ transplant rejection. Organ recipients take immunosuppressant drugs to prevent rejection, which can lead to other health problems. And sometimes, organ rejection is not recognized for many years–as much as a decade after a lung or heart has been given to a recipient. Researchers and clinicians have suspected that rejection that occurs over a long period of time, or chronic rejection is also due to an immune system attack that happens over a long period of time.

A new study has now suggested that chronic organ rejection may actually be due to problems in lymph drainage in the donor organ, and not because of the recipient’s immune system. The findings have been reported in Science Translational Medicine.

The lymphatic system is like a drainage system that moves lymph fluids from tissues back into circulation. It also generates immune cells and performs some other vital functions. 

This study, which assessed transplanted human organs and mouse models of organ transplants, found that if lymph drainage is disrupted in a donor organ when it is removed from the donor, it can lead to a cascade of problems that leads to the buildup of scar tissue, or fibrosis, in the donor organ. An analysis of rejected transplant tissue revealed that fibrosis was occurring where lymphatic vasculture was found. A sugar molecule known as hyaluronan was building up, likely due to the lymph problems, and the accumulation was causing damage.

Models indicated that if lymph drainage is restored immediately after transplant, however, the accumulation of sugar molecules in the donor organ could be prevented, and that stops the fibrosis.

While immunosuppression can help the recipients of transplanted organs, there are many who still experience chronic organ rejection, sometimes after they have been relatively healthy for years. Increases in immunosuppressive drugs are typically ineffective, which has confounded clinicians and researchers, noted senior study author Daniel Kreisel, MD, Ph.D., a professor and chair, among other appointments at the Washington University School of Medicine in St. Louis.

"We have no effective treatment for chronic organ rejection short of re-transplantation, for which many patients are not eligible," said Kreisel. "We are excited about this study because it reveals a previously unknown cause of chronic rejection that is independent of the immune response against foreign tissue, and our data show it may be treatable."

Although blood vessels are reconnected when an organ is transplanted into a recipient, the lymphatic vessels are not, partly because surgeons can’t see them. It’s thought that severed lymphatic vessels heal themselves within a few weeks of transplant.

"Even though the vessels grow back, we now see that the two-to-three-week period of disruption after the transplant is a critical window that can lead to long-term detrimental consequences for the organ," said first study author Hailey Shepherd, MD, a WashU Medicine surgical resident. "But this window also creates an opportunity to intervene to help the lymphatics heal and perhaps prevent the chronic damage we see in these rejected organs."

Improving lymphatic drainage could be a great way to help transplant recipients stay healthy without major immunosuppressive drugs. While this work was conducted in mouse models, the team is hopeful that it will translate to human patients, although more research will be needed to confirm that. 

"Our challenge now is to define the best next step to take it to the clinical setting for our patients," said Kreisel.

Sources: Washington University School of Medicine in St. Louis, Science Translational Medicine