New strategy for preventing organ transplant rejection shows promise

Organ transplantation has been one of the greatest successes of modern medicine. But one of its largest limitations comes from a patient’s immune system treating the new heart, or lung, or liver like a foreign invader.

In order to protect the donated organ, many transplant patients spend the rest of their lives on drugs to suppress their immune systems — and still their body’s efforts to fight the outsider can slowly damage the transplanted tissue, leading to chronic rejection.

Researchers at the University of Michigan Life Sciences Institute and U-M Health System Department of Surgery, however, see promise in a new approach to increasing long-term survival — one that’s showing encouraging results in animal models.

Interrupting a key cellular signaling pathway for a short period of time immediately after transplantation significantly decreased rejection in a mouse model of heart transplantation, according to findings published in the Journal of Immunology.

The research identified a major role in rejection played by two proteins involved in the Notch pathway — the Dll1 and Dll4 ligands — making them attractive as potential drug targets, said study senior co-author Ivan Maillard, M.D., Ph.D., an associate research professor at the LSI, where his lab is located, and an associate professor in the Division of Hematology-Oncology at the U-M Medical School.

D. Keith Bishop, Ph.D., the study’s other senior author and, until his recent retirement, professor in the Department of Surgery at the U-M Medical School, notes that the Notch pathway appears to play a central role in the regulation of the body’s reaction to a transplant — making it important to better understand how the pathway is controlled, and how it interacts with other regulators of the body’s immune response.

The study also builds on Maillard’s previous work that showed inhibiting the pathway could help prevent graft-versus-host disease, an often deadly complication of bone marrow transplantation.