Transplanting hope for T cells
The happiest days for Dr. Louise Markert are when she opens her mail and finds a photograph of a grinning youngster. It’s evidence that the painstaking research she began 10 years ago has been well worth it.
“I just love that -- getting the school pictures,” says the pediatric immunologist at Duke University Medical Center in Durham, N.C. “I go around the hospital with their pictures in my pocket.”
Since 1993, Markert has been conducting experimental thymus transplants on babies with DiGeorge syndrome, a rare genetic disorder that causes abnormalities of the thymus gland, heart and parathyroid gland. The thymus is essential for the production of T cells that help the body fight infection; without functioning T cells, babies with DiGeorge typically die.
A study of 12 thymus transplants conducted at Duke has shown that the treatment is effective, and Markert and her colleagues now are exploring whether thymus transplants could help other people with low T cell counts.
Markert began the work in 1992 soon after answering the telephone in the medical center’s pediatric immunology department. The caller was a doctor from Tennessee who had an infant patient with DiGeorge. About 1 in 4,000 U.S. babies is born each year with varying degrees of the syndrome, and five to 10 of those children are born with no thymus gland, a condition called complete DiGeorge syndrome.
At the time, there were no good treatments for such babies. (Some babies now can be treated with a transplant of a sibling’s bone marrow, which produces T cells.) “I thought, ‘If we at Duke can’t help this baby, who can?’ ” she says.
Markert studied the condition and suggested a thymus transplant, an idea that was first proposed by a Vermont doctor in the 1960s. Thymus transplants weren’t successful then, but Markert thought that advances in immunology had made the idea worth re-investigating. Using donated thymus tissue, she began to try to grow the tissue in a culture medium, testing it for impurities (such as viruses) so that it could then be transplanted safely into babies without a thymus. At first, the tissue samples never made it out of the lab.
“Louise would come to the lab with the tissue, and we would try to grow it in chunks. That wouldn’t work,” recalls Dr. Barton F. Haynes, director of Duke’s Human Vaccine Institute, who assisted Markert in the difficult early research. “Then we did slices of tissue and that worked better. We kept working on it, and finally we had tissue that looked happy in culture.”
By the time Markert was ready to try a transplant, the baby in Tennessee had died. The first transplant took place shortly thereafter, however. “The first transplant was truly amazing,” Haynes says. “Humans are not made to survive outside the womb without an immune system. To keep the child safe while the immune system is developing is an extraordinary achievement.”
During surgery, thin slices of thymus tissue are sewn into the baby’s quadriceps muscle (the large muscle in the thigh). If the transplant works, the tissue will survive and begin to produce T cells, enabling the child’s immune system to function properly. It doesn’t matter that the thymus tissue is transplanted far from where it usually is in the body.
“You need a good blood supply, because you want capillaries to grow right in and keep the tissue alive,” Markert says. Once the body begins to make T cells, the infants develop a normal immune system that appears to work long term, Markert says. Seven of the 12 infants in her study have survived, although some have other health problems linked to DiGeorge syndrome. The five who died all had other underlying problems related to DiGeorge.
Markert now is turning to other conditions. Transplants may help babies born with a very small thymus that doesn’t churn out enough T cells, as well as babies who need heart or lung transplants. Because new organs often are attacked by the immune system, thymus tissue taken from the donor may help the transplant recipient avoid graft-versus-host reaction. In theory, thymus transplants could help people with low T cell counts, such as some HIV patients.
“I’m hoping this will help with a number of different disorders in the future,” Markert says.
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About the thymus
Located in the upper chest cavity, the thymus gland extends upward into the neck to the lower edge of the thyroid gland. T cells -- critical to immune system function -- mature and adopt their infection-fighting role while in the thymus.
The gland is largest relative to body size when an individual is 2 years old, but it continues to grow until puberty, then it begins to shrivel. Fatty tissue eventually replaces much of the thymus, but T cells matured in the thymus earlier in life continue to provide immunity by constantly dividing.
