New research from the University of Minnesota Medical School has revealed a new mechanism by which the immune system may accept transplanted organs. The study, published in Science Advances, indicates that T cell exhaustion—a process usually seen as a failure of the immune response—can help the body tolerate donor organs.
The researchers found that the spleen plays a central role in this process. By administering apoptotic donor leukocytes (ADLs), they observed an increase in donor-specific regulatory T cells, known as Tr1 cells. These cells reduce immune activity against the transplanted organ through a pathway called Areg–EGFR, allowing for tolerance without widespread immunosuppression.
"Most transplant patients need lifelong drugs that suppress their entire immune system. What we found is that the spleen can act like a training center - but only when it's properly instructed," said Amar Singh, PhD, assistant professor at the University of Minnesota Medical School. "By programming the immune system to accept a transplant rather than suppressing it indefinitely, this approach has the potential to reduce long-term complications and meaningfully improve quality of life for transplant recipients."
Instead of weakening overall immunity, this method targets specific T cells likely to cause rejection while maintaining general infection-fighting abilities and supporting long-term graft acceptance.
"Long-term immunosuppression carries significant risks, often compromising the benefits of a transplant. Insights on the mechanisms of operational tolerance identified in this study could eliminate the need for prolonged immunosuppression, thereby improving the quality of life of transplant recipients," said Sabarinathan Ramachandran, PhD, associate professor at the University of Minnesota Medical School.
"Tolerance - often regarded as the Holy Grail of transplantation - has been the central focus of our research, aiming to ensure that patients with diabetes can benefit from islet transplantation without the burden of chronic immunosuppression," said Bernhard Hering, MD, professor at the University of Minnesota Medical School.
Future research will explore how spleen-centered immune programming might be used for other conditions where selective regulation is needed instead of broad suppression.
This work received funding from several organizations including grants from the National Institute of Allergy and Infectious Diseases, support from the University of Minnesota Foundation, Diabetes Research and Wellness Foundation and Minnesota Lions Diabetes Foundation.
