Rebuilding the Immune System Through Thymus Transplants
DURHAM, N.C. -- A piece of tissue often sliced out and discarded during infant heart surgery may have the potential to revive the battered immune systems of AIDS patients, according to doctors at Duke University Medical Center.
In an experimental treatment devised by Dr. Louise Markert, and colleagues Dr. Barton Haynes, Dani Bolognesi, Dr. John Bartlett, Dr. Charles Hicks and Kent Weinhold, doctors will implant thin slices of thymus tissue into eight AIDS patient volunteers. The experimental treatment is an effort to rev up the floundering immune system of AIDS patients by replacing a shriveled, HIV virus-riddled thymus with a healthy new one.
The thymus is the birthplace of mature infection-fighting immune system cells called T-cells. HIV wrecks havoc on the immune system by destroying the body's reservoir of mature infection-fighting T-cells. But in addition, researchers believe HIV also attacks the thymus itself. When doctors examine the thymus of a person who has died of AIDS, they often find it has shrunk, or in some cases, has disappeared completely.
The complete family of immune fighting T-cells is called the body's "T-cell repertoire." As HIV destroys more and more T-cells, doctors worry that the body's T-cell repertoire, its ability to respond to lots of different infectious agents, is diminished. In the blood, copies can be made of existing T-cells. But functioning thymus tissue is required to recreate a normal repertoire after most of the body's T-cells are destroyed.
If an AIDS patient is treated with drugs that kill the HIV virus, new T-cells can be made by copying the ones that are left. But if the patient is treated after most of the T-cells are destroyed, the increase in T-cells may represent only a few different kinds. The patient may not have a normal repertoire and will not be protected against many types of infection.
The Duke researchers' strategy is to first knock down the level of HIV virus in the blood to near zero with a potent combination of three HIV fighting drugs -- AZT, 3TC, and Ritonavir. Then the researchers will transplant thymus tissue into a patient's arm or leg muscle, which will supply the thymus with the rich blood supply it needs to function. The hope is that the new active thymus will be able to churn out T-cells and reconstitute a healthy immune system.
"By keeping the viral load under control with these medicines, the thymus is protected and can produce new T-cells," said Markert, director of Duke's General Clinical Research Center and assistant professor of pediatrics.
Doctors normally measure the loss of AIDS patients' T-cells in quantity, not in quality. The Duke team will measure the loss of specific T-cells in a controlled experimental setting, Markert said. They will evaluate whether the patients have lost their ability to recognize tetanus toxin, because almost everyone has had a tetanus shot. They will also immunize the patients against a foreign, noninfectious protein that humans are normally not exposed to. The doctors will see if patients can generate new T-cells that recognize the protein before and after they receive a new thymus.
In people, the thymus sits over the top of the heart like a cap. To gain access to the heart during surgery, doctors routinely remove part of the thymus and discard it.
For this study, doctors will ask the parents of infant heart patients if they will donate the discarded thymus tissue to transplant it into the AIDS patients. If parents give permission, the doctors will save the thymus and test it to make sure it is free of infectious viruses before implanting it into patients. The doctors chose infants because early in life the thymus is vigorously active, churning out T-cells that will protect the body against infection and disease for a lifetime. As we age, the thymus slowly becomes less active because it has mostly completed its job of generating a large variety of unique T-cells that can fight most infectious agents.
Markert has already shown that transplanted thymus can work. She conducted successful thymus transplants in three children born without a functioning thymus. The disorder, called DiGeorge syndrome, leaves the body defenseless against infection. All three patients who received transplants at Duke developed healthy, functioning immune systems.
Other researchers have tried thymus transplants for AIDS patients, but those patients weren't being treated with antiviral drugs. The HIV virus probably infected the transplanted thymuses and quickly destroyed them, Markert said.
The entire procedure will pose little danger to the patients, Markert said. The thymus will be transplanted into the arm or leg muscle with only local anesthetic. The researchers will monitor whether there is any rejection of the new thymus, because AIDS patients' immune systems are reduced, but not to zero, Markert said.