Currently, people receiving organ transplants must take drugs to suppress the inflammatory immune response that leads to rejection. Even so, almost all recipients eventually lose their transplant.

A new approach, which maintains a population of immune cells that naturally temper immune responses, could greatly enhance people's long-term tolerance for transplants, report researchers at Boston Children's Hospital.

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. 

"We got prolonged graft survival in the mice, similar to what you would see with standard immunosuppressants," said David Briscoe, MB, 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).

Curbing the inflammatory response

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.

"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 Johannes Wedel, MD, a postdoctoral fellow in the Briscoe lab and first author on the paper.

"But when we turn on DEPTOR, they do not do that—they remain stable and active, and potently inhibit rejection-causing effector cells," said Wedel.

Deconstructing DEPTOR

To better understand how DEPTOR functions in T cells, Briscoe and colleagues collaborated with David Sabatini, of the Whitehead Institute for Biomedical Research, and Mathieu Laplante, now at Université Laval (Quebec City), who originally identified DEPTOR in other cell types.

Wedel worked with Peter Sage, Ph.D., of Harvard Medical School, to sequence Tregs' messenger RNA to see what genes DEPTOR was turning on and off. Many of the genes that came up as "hits" are involved in cell metabolism.

Drug treatment for transplant and autoimmune disease?

Briscoe thinks the study findings also have potential implications for treating autoimmune disease. "Classically, Tregs are not fully functional in autoimmune diseases," he said. "So enhancing Treg stability or activity could help."

Briscoe envisions two possible forms of treatment. The drugs, with some formulation work, could be designed to be given to patients directly, along with immunosuppressants, to maintain a stable, functional pool of Tregs that suppress rejection.

Alternatively, Tregs isolated from a patient's blood could be manipulated genetically or treated with a DEPTOR-enhancing drug to make them more stable, then reinfused back into the patient.