Monday, June 02, 2003

By Anita Srikameswaran, Post-Gazette Staff Writer

Children who receive heart transplants have dramatically fewer episodes of organ rejection if donor bone marrow is injected into their thymus glands at the time of surgery.

Researchers led by Dr. Steven Webber of the University of Pittsburgh School of Medicine and Children's Hospital also learned that these children require fewer anti-rejection drugs.

They presented the findings yesterday in Washington, D.C., at the American Transplant Congress.

Giving bone marrow during organ transplantation is one way researchers are trying to help the immune system become tolerant of foreign organs. If they succeed, patients might be able to lower their doses of anti-rejection drugs or stop taking them. In the long term, the drugs can cause serious complications.

In acute rejection, immune cells called T-cells attack the donor organ. Some experts suggest that fewer acute rejection episodes might mean that the transplant recipient is less likely to develop chronic rejection, which in the heart results in an untreatable form of coronary artery disease.

"The most common cause of death beyond the first couple of years after transplant in children and adults is progressive coronary artery disease," Webber said.

He added that 30 percent to 50 percent of adult patients and 10 percent to 15 percent of pediatric patients develop the artery disease within five years of transplantation. Because the nerves supplying the heart are cut during surgery and cannot be reconnected, patients don't typically have angina pain as a warning sign. The first evidence of chronic rejection could be a heart attack or even sudden death.

For the study, doctors injected donor bone marrow into several places in the patient's thymus gland during the transplant operation.

The thymus plays a key role in the immune system; it is there that immature disease-fighting cells called T-cells are activated. Scientists think that T-cells that target the body's own tissue, or "self," are destroyed in the gland. Injecting donor bone marrow, which contains donor immune cells, into the thymus could trick the gland into eliminating T-cells capable of attacking the donor heart.

Mature T-cells in the bloodstream could still attack the organ, so the researchers didn't expect to eliminate acute rejection episodes immediately.

"We didn't really see any early differences in terms of the number of rejections in the first six months," Webber said. "Beyond six months, there's actually fairly wide differences in what I call late rejection episodes."

Between six months and one year after surgery, there was one case of acute rejection among the 14 heart transplant patients who got bone marrow treatments, and six cases among the 22 children who did not get the cells. A year or more after the surgery, there was one acute rejection episode in the bone marrow group and 22 episodes among the other group.

Sixty percent of children in the bone marrow group are taking one anti-rejection drug, compared with 26 percent of patients in the other group. The researchers will keep monitoring the children to track rejection and medication use.

The thymus gland shrinks after puberty and its activity dwindles with age, so the technique has more promise in children than in adults.

Because of the small number of patients, it will be difficult to prove whether or not the thymic injections result in fewer cases of chronic rejection. In adult patients, scientists have been working with sophisticated ultrasound imaging to assess artery narrowing. The technique could evolve into something suitable and safe to use in the smaller blood vessels of children.

In six to 12 months, the researchers will change the anti-rejection drug regimen in new study volunteers to one that is more likely to promote organ tolerance and thus reduce chronic rejection, Webber said. A drug that reduces the numbers of circulating mature T-cells will likely be given at the time of the heart transplant procedure.

Anita Srikameswaran can be reached at anitas@post-gazette.com or 412-263-3858.