Heart transplants survive longer in mice with genetically enhanced DEPTOR, a regulatory protein in immune cells. The study was conducted at Boston Children's Hospital and published in the July 3 issue of the American Journal of Transplantation.

In the experiment, mice that received heart transplantations but no immunosuppressive drugs survived an average of seven days. However, mice treated with genetically enhanced DEPTOR activity in their T cells survived an average of 35 days.

"We got prolonged graft survival in the mice, similar to what you would see with standard immunosuppressants," said Dr. David Briscoe, director of the Transplant Research Program at Boston Children's and the study's senior investigator.

More significantly, when the mice with DEPTOR enhancements were given immunosuppressive drugs, the survival rates increased much more dramatically. The mice survived 100 days or longer, which the study team defined as developing "organ tolerance."

The body's immune system has two types of T cells: effector T-cells and regulatory T-cells, called Tregs. The Tregs act to resolve or suppress inflammation during an immune response. The immune system maintains a mix of these cells, but after transplantation, a number of the Tregs may switch to effector cells.

Immunosuppressive drugs act to diminish the response of effector T-cells. This study shows that boosting DEPTOR activity within Tregs may prolong their lifespan and keep them from switching to effector T-cells.

"Normally, when a recipient's immune system 'sees' a transplant, Tregs are overwhelmed by the effector T-cell response and cannot shut down inflammation. They may even become effector cells," said Dr. Johannes Wedel, a postdoctoral fellow in the Briscoe lab and first author on the paper. "But when we turn on DEPTOR, they don't do that — they remain stable and active, and potently inhibit rejection-causing effector cells."

Enhancing DEPTOR seems to work only on the Tregs. It had no impact on effector cells' immune response following transplantation.

To determine how DEPTOR works in the immune response, Tregs' messenger RNA was studied to determine which genes DEPTOR was turning on and off. Many of the identified genes are involved in cell metabolism.

"Metabolism of T cells is very important to their function," Wedel said. "By boosting the activity of DEPTOR, we can shape metabolism in a direction that makes regulatory T cells much more stable and more active."

While this study didn't use a pharmaceutical method to "turn on" DEPTOR, Briscoe said it may be possible to use a drug to boost DEPTOR.

Specifically, compounds called Cullin-RING E3 ligase inhibitors increase DEPTOR activity by keeping it from being destroyed. A second method may involve isolating Tregs from a patient's blood, infusing it with DEPTOR-boosting drugs and then reinfusing it to the patient.

"We are interested in identifying specific DEPTOR enhancing agents and moving this area of research forward in pre-clinical models," Briscoe said.

Briscoe and Wedel are currently studying DEPTOR to gain a better understanding of how it works in relation to Tregs and the body's immune response to different disease models.