Donor-Derived Cell Therapy Enables Immunosuppression Withdrawal in Liver Transplant Patients
核心洞察
UPMC researchers successfully weaned four liver transplant patients off all immunosuppressive drugs for over three years using donor-derived regulatory dendritic cells (搜索).
The phase I/IIa trial achieved a 37.5% tolerance rate among eligible patients, significantly higher than the historical 13% rate in standard care recipients.
The innovative approach involves infusing recipients with donor immune cells one week before transplantation to train the immune system to accept the new organ.
UPMC and University of Pittsburgh clinician-scientists have achieved a significant breakthrough in transplant medicine by successfully weaning multiple liver transplantation (搜索) patients off all immunosuppressant drugs (搜索) for more than three years. The achievement comes through a first-in-human clinical trial of an innovative "immune priming" therapy using donor-derived immune cells.
The results, published in Nature Communications, demonstrate 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, followed by gradual removal of immunosuppression drugs one year later in eligible patients.
Novel Approach to Immune Tolerance
The phase I/IIa trial, launched in 2017 with funding from UPMC Enterprises (搜索), recruited and followed 13 living donor liver transplant (LDLT) patients. The innovative approach leverages the liver's unique ability to regenerate, allowing healthy donors to provide a portion of their liver while both parts regrow into full organs.
"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 (搜索)," said senior author Angus Thomson, Ph.D., D.Sc., Distinguished Professor of Surgery and Immunology in Pitt's School of Medicine.
The research team, led by first author Abhinav Humar, M.D., clinical director of the Starzl Transplantation Institute (搜索) and chief of the Division of Transplantation at UPMC, developed a protocol to train recipients' immune systems to accept donor organs as friendly rather than foreign.
Treatment Protocol and Mechanism
A few weeks before transplantation surgery, researchers filtered white blood cells called monocytes (搜索) from the donor's blood. These monocytes were then induced to make regulatory dendritic cells (搜索) (DCregs), which teach the graft recipient's immune system to distinguish between foreign invaders and friendly cells.
The donor's DCregs were administered to recipients one week before transplantation surgery, with the expectation that they would "instruct" the immune system to recognize the donor liver as friendly and not attack it.
One year after transplantation, recipients underwent testing to determine if they had immunological signals conducive to removing immunosuppression without risking organ rejection (搜索).
Clinical Outcomes
Of the 13 trial participants, eight were eligible for immunosuppression withdrawal. Four patients achieved complete withdrawal of immunosuppression, with three remaining off 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, compared to approximately 13% in historical non-trial adult liver transplant recipients deemed eligible for early withdrawal.
However, the researchers emphasize that while promising, the results are exploratory and not definitive because the trial was not large enough nor designed to establish efficacy.
Future Research Directions
"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 findings justify future studies, most notably a larger randomized controlled 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 research team is also proposing to test different immunosuppressant medications that may be more conducive to allowing DCregs to take effect. Additional considerations include administering DCregs post-surgery to potentially improve outcomes and obtaining DCregs from deceased donors.
Clinical Significance
UPMC leads the nation in living donor liver transplants, performing 89 procedures in 2025. The current standard requires LDLT recipients to take lifelong medications that suppress their immune response, as the immune system would otherwise attack the new organ.
"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."
The research represents progress toward a three-decade goal pursued by Pittsburgh transplant scientists under the direction of the late Dr. Thomas Starzl to spare patients from the serious side effects of long-term immunosuppression.