Donor-derived dendritic cells teach the immune system to accept new livers

UPMC and University of Pittsburgh clinician-scientists have weaned and kept multiple liver transplantation patients off of all immunosuppressant drugs for more than three years through a first-in-human clinical trial of a unique "immune priming" therapy.

Results of the small, early-stage trial are reported today in Nature Communications. They confirm that it is feasible, safe and preliminarily effective to give living donor liver transplant recipients an infusion of immune cells derived from their donor a week before transplantation and then, one year later in eligible patients, start to remove the immunosuppression drugs that prevent organ rejection.

"Long-term use of immunosuppressive drugs can harm the kidneys, causes metabolic complications, makes patients more susceptible to infections and certain types of cancer, as well as diabetes," said senior author Angus Thomson, Ph.D., D.Sc., Distinguished Professor of Surgery and Immunology in Pitt's School of Medicine.

Sparing patients from these serious side effects has been a goal that Pittsburgh transplant scientists, under the direction of the late Dr. Thomas Starzl, began pursuing three decades ago. It is an honor to achieve this important milestone toward finally realizing that dream."

Angus Thomson, University of Pittsburgh

The liver has the special ability to regenerate, which means that a healthy person can donate a portion of their liver to someone whose liver is failing, and both parts will regrow into full organs. UPMC leads the nation in living donor liver transplants (LDLT), performing 89 in 2025.

However, as with almost any organ transplant recipient, LDLT recipients still need to take lifelong medications that suppress their immune response. This is because their immune system will otherwise attack the new organ, thinking that it is a foreign invader. Since a patient with end-stage liver disease will die without the new organ, the potentially serious side effects of immunosuppressant drugs are considered acceptable.

But what if the recipient's immune system could be trained to accept the new organ?

In 2017, with funding from UPMC Enterprises, Thomson and colleagues, in particular first author Abhinav Humar, M.D., clinical director of the Starzl Transplantation Institute and chief of the Division of Transplantation at UPMC, launched the phase I/IIa trial to do exactly that, ultimately recruiting and following 13 LDLT patients.

A few weeks before the transplantation surgery, the team filtered white blood cells, called monocytes, from the donor's blood. Those monocytes were then induced to make regulatory dendritic cells (DCregs), which teach the graft recipient's immune system to distinguish between foreign invaders and friendly cells.

The donor's DCregs were then given to the recipient a week before the transplantation surgery, with the expectation that they would "instruct" the immune system to recognize the donor liver as friendly and not attack.

A year after the transplantation surgery, the recipients were tested to see if they had immunological signals conducive to removing immunosuppression without risking organ rejection. Eight of the 13 participants were eligible and four achieved complete withdrawal of immunosuppression, with three remaining off the immunosuppressants for more than three years.

This translates to a 37.5 % rate of tolerating the transplanted organ in trial recipients eligible for immunosuppression withdrawal early post-transplant, which compares to about 13% in historical non-trial adult liver transplant recipients deemed eligible for early withdrawal. However, the researchers stress that the results, while promising, are exploratory and are not definitive because the trial was not large enough, nor designed to establish efficacy.

"For as long as organ transplantation has been a field of medicine, tolerance has been its holy grail," Humar said. "And, while we haven't hit a home run yet, we've definitely gotten on base by reliably and safely removing immunosuppression early after transplantation from a significant percentage of patients, which is a huge breakthrough."

The researchers explained that the findings justify future studies, most notably a larger randomized control trial that would assign half the transplant patients to receive DCregs and the other half to standard-of-care, allowing for a true head-to-head comparison of results. The team is also proposing to test a different immunosuppressant medication than what is usually used because it may be more conducive to allowing the DCregs to take effect. They could also give the DCregs post-surgery to see if that would improve outcomes and even consider obtaining DCregs from deceased donors.

"There are so many tantalizing paths we could take to help our findings benefit many more patients," Thomson said. "We are very interested in collaborating with other transplantation centers to accelerate and scale our clinical research."