Spleen-driven immune tolerance may protect transplanted organs

New research from the University of Minnesota Medical School offers a new view of how the immune system responds to organ transplants. The findings, published today in Science Advances External link that opens in the same window, show that T cell exhaustion – traditionally viewed as a pathological failure of the immune system - can instead play a protective role by helping the body tolerate a donated organ.

The study identifies the spleen as a key control center for transplant tolerance. Researchers found that administering apoptotic donor leukocytes (ADLs) triggers the expansion of donor-specific regulatory T cells, known as Tr1 cells. These cells help calm the immune response by limiting the activity of T cells that would otherwise attack the transplanted organ, using a signaling pathway called Areg–EGFR. This targeted process allows immune tolerance to be established without broadly suppressing the immune system.

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. 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."

Amar Singh, PhD, assistant professor, University of Minnesota Medical School

Rather than weakening the immune system overall, the approach induces a controlled, donor-specific state in the T cells most likely to cause rejection. This spleen-based regulatory circuit preserves the body's ability to fight infections while still 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, an 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 studies will focus on leveraging spleen-centered immune programming to promote durable transplant tolerance and to explore broader applications in immune-mediated diseases where selective immune regulation, rather than suppression, is needed.

This research was funded by the National Institute of Allergy and Infectious Diseases [grant numbers U01AI102463, U19AI174966, R21AI166163, R21AI190721], the University of Minnesota Foundation, Diabetes Research and Wellness Foundation and the Minnesota Lions Diabetes Foundation.