In a study published July 3 in the American Journal of Transplantation, increasing the activity of a regulatory protein called DEPTOR in immune cells enabled heart transplants to survive in mice much longer than usual.
In initial experiments, the mice received no immunosuppressive drugs, and heart transplants survived for an average of 7 days. But in mice with genetically enhanced DEPTOR activity in their T cells, average transplant survival was 35 days.
Graft - Survival - Mice - Immunosuppressants - David
"We got prolonged graft survival in the mice, similar to what you would see with standard immunosuppressants," says David Briscoe, MB, ChB, director of the Transplant Research Program at Boston Children's and the study's senior investigator.
The most exciting results came when DEPTOR enhancement was combined with immunosuppressive drugs. These mice appeared to develop transplant tolerance: their transplants survived almost indefinitely (100 days or longer).
Immune - System - Arms - Arm - Effector
The immune system has two arms: An inflammatory arm, led by effector T-cells, and a regulatory arm, led by regulatory T cells or Tregs, which resolve or suppress inflammation. The immune system maintains different mixes of effector and regulatory T-cells, depending on the situation. After transplantation, the balance generally shifts toward effector cells, and existing Tregs can switch to the effector type.
Standard immunosuppressive drugs suppress transplant rejection by curbing effector T-cell responses. But the study suggests the possibility of adding a second approach: enhancing and stabilizing the regulatory T-cell response via DEPTOR. In multiple experiments, boosting DEPTOR activity within Tregs made them more long-lived and functional.
Recipient - System - 'sees - Transplant - Tregs
"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," says Johannes Wedel, MD, PhD, 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...
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