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July 5, 2006 -- No. 334
Study: Targeting specific immune cells may help
reduce rejection of skin grafts in burn patients
CHAPEL HILL - Burn patients, such as a man currently in the North Carolina
Jaycee Burn Center who was burned over 90 percent of his skin, are among the
most vulnerable to infection. Their injuries have traumatized their immune systems.
"Infection is the leading cause of death in these patients. Patients with large burns have a 100 percent chance of getting pneumonia," said Dr. Bruce A. Cairns, assistant professor of surgery and of microbiology and immunology in the University of North Carolina at Chapel Hill School of Medicine.
When patients can't receive grafts of their own skin to close their wounds, doctors use donated skin. But, at best, these grafts serve as temporary wound covers. The patient's immune system rejects donated skin in a matter of weeks.
"There's no way that you can right now safely induce tolerance or acceptance of a skin graft for a burn patient," said Cairns, who is also director of the intensive care unit and director of research at the Jaycee Burn Center.
But how these patients' immune systems reject skin grafts when they can't fight off infection is a question that has gone largely unanswered since the first attempts at skin grafts were made during World War II.
Now Cairns and colleagues have found part of the answer. Their work in a mouse model suggests that the very mechanism by which a burn patient's body attempts to recover - the hyperactivity of immune system cells called CD8 T cells - causes the body to reject a skin graft.
The scientists also showed that they could slow down rejection of skin grafts by using RU486 (the drug known as "the abortion pill") to block stress hormones called glucocortoids.
Blocking these hormones inhibited the initial cell death (apoptosis) of CD8 T cells that happens immediately after a burn, in turn blocking the "bounce back" hyperactivity that normally happens about 14 days after a burn.
The study, published in the June issue of the Journal of Immunology, suggests that it may be possible to selectively target only the cells that are responsible for skin graft rejection without compromising other functions of the immune system.
More research is needed to determine whether it would be safe to manipulate the immune system in this way. "While blocking apoptosis has an attractive element to it, it may also cause problems down the road in terms of being able to fight infection. It's possible that cells that die, should die," Cairns said.
Along with Cairns, authors on the study are first author Dr. Robert Maile, research assistant professor in the UNC departments of surgery and microbiology and immunology; Dr. Anthony A. Meyer, distinguished professor and chair in the UNC department of surgery; research analyst Carie M. Barnes and laboratory technologist Alma I. Nielsen, also of the department of surgery; and Dr. Jeffrey A. Frelinger, distinguished professor and chair of the UNC department of microbiology and immunology.
The findings also have implications for the current controversy surrounding facial transplants, Cairns said. "Scientists agree that one of the real barriers to facial transplants is skin graft rejection," he said. These transplants do not save lives and require recipients to take immunosuppressive drugs for the rest of their lives, putting them at risk for life-threatening infections.
"Answering these questions will help us address whether or not we can really successfully modulate the long term immune response to a face transplant," Cairns said.
The researchers performed a series of experiments in mice over a period of three years. The experiments first showed that CD8 T cells, whose normal function is to fight viruses, diminished in numbers immediately after a burn.
Then the scientists showed that 14 days after the burn, CD8 T cells are still fewer in number but show heightened activity.
By taking CD8 T cells from a burned mouse and injecting them into a normal mouse, the researchers showed that it was actually the T cells that sped up skin-graft rejection. The mice who received T cells from a burned mouse rejected skin grafts faster than mice in a control group.
But when the researchers administered RU486, skin graft rejection slowed to the same rate as that of the control mice.
The research was supported by a grant from the National Institutes of Health and by the North Carolina Jaycee Burn Center.
School of Medicine contact: Les Lang, (919) 843-9687 or email@example.com