When a young child needs an organ transplant, they need to be on immunosuppression drugs for life so that they won’t reject their donor organ. This solution is far from perfect. Rejection remains a problem, and the drugs themselves come with a litany of complications like increased risk of infections, cancer, and diabetes. The median survival of children with heart transplants is just 15 years.
An international team of researchers from Canada and Spain are working together on a clinical trial that is the first in the world to try a different approach that could mean successful heart transplants without immunosuppression.
One of the leaders of the trial is BC Children’s Hospital researcher Megan Levings, also a professor of surgery and biomedical engineering at the University of British Columbia. She has spent the past two decades studying the biological mechanisms that keep the immune system in check.
Our immune system is a complex network designed to recognize foreign materials that could harm us and mount a defense against them. That’s why a donor organ can be attacked without strategies to block this unwanted immune response. Thankfully, we have regulatory T cells (also called Tregs) that normally help modulate the immune response to spare our own cells from harm, and Levings was a pioneer in demonstrating that they could be used as a therapy to stop harmful immune responses.
This is something that has been applied to research with adult patients, taking Tregs from the blood. That same approach doesn’t work for pediatric patients because it takes about half a litre of blood to get enough cells, and children don’t have the necessary blood volume to spare.
Levings partnered with Lori West, pediatric cardiologist at the University of Alberta and the Director of the Canadian National Transplant Research Program (CNTRP). West previously showed that newborns could tolerate heart transplants without rejecting them, even if they were not a blood type match. Together, they hunted for a different source of Tregs that might work for our youngest patients.
They found it in the thymus, a gland in the chest — just under the breastbone — that is routinely removed during pediatric heart transplant surgery to get better access to the heart. Normally, the thymus is simply discarded during the process.
One gram of thymus has 500 times more Tregs than one millilitre of blood, making it a concentrated source of high-quality cells. That means that a single gram of this otherwise discarded tissue would have just as many Tregs as the blood sample used for the adult procedure. Levings and West published their findings in the American Journal of Transplantation.
They took that result to Spain, a world leader in organ transplantation where 25-30 pediatric heart transplants happen every year. Rafael Correa-Rocha is a pediatric immunology researcher at the Gregorio Marañón Health Research Institute in Madrid, and he became the first to use thymic Treg therapy on a 6-month-old patient in 2020.
A week before the transplant, he harvested the patient’s thymus and grew lots of Tregs in the lab to prepare for the procedure. Today that patient is 3 years old and still thriving, maintaining normal levels of Tregs despite having her thymus removed with just that one infusion of cells. The team has since performed the procedure on four more patients, establishing safety. They published the preliminary results of their clinical trial in Transplantation. Six more patients are enrolled in the study and awaiting donor hearts.
If the rest of this first clinical trial continues to demonstrate safety, the next step is to follow up with these young patients. Their level of surviving Tregs will be measured before deciding whether immunosuppression drugs can be reduced, and possibly giving a new infusion of Tregs in cases where more are needed.
“We see the project of thymic Tregs as a platform of the future,” said Levings in a press release.
“These trials currently underway are setting the stage for future research with genetically modified cells. And this is all using a little-known organ that is in the way of pediatric heart surgeons, and just being removed and thrown away.”
