Organ Transplantation Without Long-Term Immunosuppression

Giving living donor liver transplant recipients an infusion of immune cells taken from their donor a week before transplantation is practical, safe, and may result in recipients successfully weaning off immunosuppressant drugs without rejecting the transplanted organ.

The results of an early-stage clinical trial conducted by scientists at the University of Pittsburgh School of Medicine, published today in Science Translational Medicine, point to a path that could save organ transplant recipients from the serious side effects of long-term immunosuppressant use, which can include cancer, diabetes, kidney failure, and susceptibility to infections.

“These trial results are very encouraging,” said senior author Angus W. Thomson, Ph.D., D.Sc., distinguished professor of immunology and surgery at Pitt and member of the Thomas E. Starzl Transplantation Institute. “Right now, we’re seeing preliminary evidence that this intervention is modifying the recipient’s immune response in such a way that we may be able to safely reduce — or even withdraw — immunosuppression.” It would be a tremendous benefit to the transplant community if patients were no longer dependent on immunosuppressants indefinitely.”

People can give a portion of their liver to someone else in need because the liver regenerates. Both the donor’s part of the liver and the recipient’s part of the liver regrow to full-sized livers. This is known as a living donor liver transplant (LDLT).

Thomson, in collaboration with Abhinav Humar, M.D., clinical director of the Starzl Transplantation Institute and chief of the Division of Transplantation at UPMC, and the rest of the research team, enrolled 15 patients scheduled to receive an LDLT and compared them to 40 LDLT patients who did not receive the infusion in a Phase 1 trial.

Several weeks before surgery, the research team collected blood from trial subjects’ donors and separated out the monocytes, a type of white blood cell. They next encouraged the monocytes to produce regulatory dendritic cells (DCregs), a type of immune cell that aids the immune system in distinguishing foreign invaders that must be destroyed from sections of the body that should be left alone.

The newly created DCregs were administered into the recipient patients a week before the transplant. The transplant then proceeded normally, and the patients were given immunosuppressant drugs just as if they had not received the DCregs.

The trial’s primary purpose was to assess feasibility and safety. There were no changes in safety between DCreg infusion patients and standard-of-care patients. Furthermore, it was possible to include the DCreg infusion into the clinical process while still conducting the transplantation on time.

However, the researchers went one step further and looked for changes in immunologic activity between the two patient groups. A year later, they discovered that patients who had the DCreg injection also exhibited a decrease in other immune cells that would indicate a negative reaction to the transplanted liver. This lowering has allowed researchers to successfully wean animals off immunosuppressants in animal experiments.

Surprisingly, the transplanted DCregs barely lasted a few days in the recipient patients. However, they were able to manufacture microscopic particles called exosomes at the time, which allow cells to communicate by transmitting messages from one cell to another, influencing a range of cellular responses.

“We believe that these donor-derived exosomes are preemptively conditioning the prospective LDLT recipient to see donor cells as safe,” said Thomson. “A year post-transplant, clinicians will then determine which patients can start tapering off immunosuppressants. Then time will tell if our approach works.”

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