Transplant Tolerance

October 22, 2015

Columbia researchers have pinpointed the immune system mechanism that allows a kidney transplant to be accepted without lifelong immunosuppressant drugs, a significant step toward reducing or eliminating the need for the costly and potentially toxic immunosuppressant drugs and improving long-term transplant success.

Using a new technique for identifying and tracking specific cells, combined with advanced genetic sequencing, the researchers found a set of patient-specific T cells that react to the donor tissue. In patients who reject the organ, these cells increase in number. The cells gradually disappear, however, in patients who accept the organ without immunosuppression; those patients are considered to be immunologically “tolerant” of their donors.

“This new technique has the potential to predict and identify rejection and tolerance in different types of transplant patients,” says study leader Megan Sykes, MD, the Michael J. Friedlander Professor of Medicine, professor of microbiology & immunology and surgical sciences (in surgery), and director of the Columbia Center for Translational Immunology.

When a patient receives a transplant, a unique population of lymphocytes, donor-reactive T cells, emerge to reject the foreign organ. Immunosuppressant medication is almost always required to prevent rejection of the donor tissue.

Earlier studies suggested that a unique subset of T cells, called regulatory cells, play a role in inducing tolerance, but they seemed not to be involved in maintaining tolerance later on. Furthermore, it was unclear whether donor-reactive T cells actually disappeared or were still present but inactive in long- term tolerant recipients. To learn more, the Columbia team devised a new technique for identifying and tracking these cells.

The researchers used their technique on blood samples taken from six kidney transplant patients. Two of the patients had undergone conventional kidney transplants. The other four received combined kidney and bone marrow transplantation (CKBMT) in a clinical trial and stopped taking immunosuppressants eight months after surgery. CKBMT, an experimental therapy, produces an immune state that combines elements of both the recipient’s and donor’s immune systems. “Our studies have shown that CKBMT induces tolerance of the transplanted organ without the need for long-term immunosuppressants. But we didn’t understand the mechanism behind this tolerance,” says Dr. Sykes, who helped develop CKBMT in the early 2000s as part of a Harvard University–Massachusetts General Hospital team.

In the new study, Columbia researchers identified the donor-reactive T cells in each patient’s blood before transplant and repeated the test after transplant at six, 12, and 18 months. Three of the four patients who underwent CKBMT showed a decrease in donor-reactive T cells and tolerated the transplant. In the fourth CKBMT patient, the donor-reactive cells did not significantly decline over time and the patient rejected the donor kidney. The two patients who had the kidney transplant alone had an increase in donor-reactive T-cell receptors.

“Our findings suggest that deletion of a specific set of donor-reactive T cells is a major mechanism governing tolerance of donor tissue,” says Dr. Sykes. “The study also supports the approach of combining kidney transplants with bone marrow transplants, with its resultant elimination of donor-reactive T cells. This approach needs further study, but so far, all signs indicate that it could eliminate the need for lifelong immunosuppression.”

Immunosuppressant drugs have dramatically increased transplant success, but they have notable drawbacks, including significant side effects and increased risk of cancer, opportunistic infections, hypertension, elevated cholesterol, and other conditions. “On top of all that, the transplants often do not survive permanently because of the drugs and the constant attacks of the recipient’s immune system,” says Dr. Sykes. The team is planning a trial of CKBMT at Columbia.

This is a summary of research published in Science Translational Medicine, Jan. 28, 2015.