February 2001

From University of Texas Southwestern Medical Center at Dallas

Researchers discover thymus gland plays role in fighting infection after bone-marrow transplantation

DALLAS - March 1, 2001 - The thymus gland, until recently thought to be inactive after childhood, plays an important role in immune system reconstitution after bone-marrow transplantation, researchers at UT Southwestern Medical Center at Dallas have discovered.

In a paper published in today's issue of Blood, the journal of the American Hematological Society, the researchers report that the thymus continues to function in adulthood and can affect a patient's recovery from allogeneic stem-cell transplantation. In allogeneic transplants, the patient receives a donation of stem cells or bone marrow from a donor, usually a close relative. Many of those patients develop graft-vs.-host disease, in which the new donor-derived immune system recognizes the recipient's body as foreign.

The thymus gland produces T-cells, which fight infection and thus help patients recover from a transplant.

"T-cells are one of the most important parts of the immune system. They are white blood cells that are responsible for 'coordinating' the body's immune response against viruses, parasites and bacteria. They are essential," said Dr. Daniel Douek, assistant professor of internal medicine at UT Southwestern.

Although previous studies showed the thymus was only active in childhood and then atrophied, in 1998 these UT Southwestern researchers reported in Nature that the thymus gland continues to produce T-cells throughout life. Their study involved patients with damaged immune systems due to HIV.

In the Blood paper, the researchers looked at the role of the thymus gland in immune reconstitution after bone-marrow or stem-cell transplants in people who have been treated for leukemia. Chemotherapy depletes T-cells in these patients.

"It's important because if you want to end up with a normal immune system - like the immune system of a healthy child - you need your thymus," said Douek. "The young immune system has a broad repertoire; it can recognize a wide range of viruses. The older you get, the more skewed the repertoire gets due to exposure to more and more diseases. If you get exposed to a flu virus, for example, many T-cells will respond to that flu virus and proliferate, and your immune system will be weighted toward that flu virus."

In a study published last year in The Lancet, UT Southwestern researchers studied patients who had received autologous bone-marrow transplants, meaning they received their own bone marrow after chemotherapy. They found that in these patients, ranging in age from 34 to 66, their thymuses reconstituted their immune systems.

The most recent study involved patients who received the more common allogeneic transplants. "What we asked in this study was: Does the thymus help make a new immune system after allogeneic bone-marrow transplants? We found that the answer was yes, it does; it contributes an enormous amount, especially in children," Douek said. The researchers then looked at the major factors affecting thymic output "so that if there are things that inhibit thymic output, we can try to clinically prevent that from occurring."

"We found that with increasing age, thymic output decreased, which is what we would have expected. Most importantly, we found that graft-vs.-host disease completely shuts off output of new cells from the thymus," he said. "We know thymic output is beneficial; we know that it occurs; and we know the most damaging thing to thymic output is graft-vs.-host disease. You have to try to fight GVHD if you're going to reconstitute a new immune system with a broad repertoire."

GVHD is treated with immunosuppressive drugs, and the researchers found that those drugs do not inhibit thymic output, he added. This means GVHD could be treated early and aggressively without impairing thymic output. Douek said the next step is to study the pathways of immune reconstitution to aid in the development of various compounds for use in clinical trials.

"This sets the groundwork for clinical trials to improve immune reconstitution," Douek said. The study included 67 patients, from infants to adults, at four medical centers: UT Southwestern, Children's Hospital of Los Angeles, Fairview-University Medical Center in Minneapolis and Baylor University Medical Center in Dallas.

Participating researchers from UT Southwestern were Brenna J. Hill, research assistant in internal medicine; Dr. Richard A. Koup, chief of infectious diseases; Dr. Michael R. Betts, fellow in internal medicine; and Dr. Robert H. Collins, associate professor of internal medicine and director of UT Southwestern's bone-marrow transplant program. Other researchers involved were Drs. Kenneth Weinberg and Monika Smogorzewska of Children's Hospital of Los Angeles, Drs. Bruce R. Blazar and John E. Wagner of the University of Minnesota School of Medicine, and Dr. Edward Agura of Baylor University Medical Center.

The research was funded in part by the Leukemia and Lymphoma Society of America.











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