July 3, 1998 GENEVA, Switzerland--Emory University research into the role of the thymus in HIV--particularly in children--has uncovered new knowledge that may lead to improved diagnosis, prognosis and possibly treatment for some pediatric patients.
At this week's 12th World AIDS Congress in Geneva, Switzerland, Andre J. Nahmias, M.D., M.P.H., director, Division of Infectious Diseases, Epidemiology and Immunology, Department of Pediatrics, Emory University School of Medicine, reports on a study of thymus transplants in four children with advanced cases of AIDS. The transplants were first performed in 1993 and were the first thymic transplants for pediatric AIDS patients.
New technologies had been developed by Dr. Richard Hong, University of Vermont, a collaborator, which permitted improvements in thymic transplants for infants born without a thymus (DiGeorge Syndrome). All four AIDS children were critically ill at the time of transplant and only one of the children has survived for more than four years. The surviving child was then 11 years old and had contracted AIDS at one year of age from a blood transfusion during heart surgery. He was suffering from multiple opportunistic infections and was declining rapidly, Dr. Nahmias reports. Today, the boy is alive and has no visible symptoms of AIDS.
While the thymus organ, located in the chest, becomes virtually nonfunctional in older age, it serves the important function in children of producing T lymphocytic immune cells.
In particular, it produces the CD4+ helper T cells that are depleted by the AIDS virus; it also produces CD8+ cytotoxic T cells. Both types of cells are involved in resistance to HIV, as well as to many other microorganisms.
In 1996, Dr. Nahmias and Athena P. Kourtis, M.D., Ph.D., reported in the New England Journal of Medicine on research about thymus dysfunction in pediatric AIDS patients and how thymus dysfunction might be used as a method of identifying those HIV+ infants who are at highest risk for rapid and aggressive development of AIDS, in contrast to patients in whom symptoms might not appear for a number of years.
Drs. Nahmias and Kourtis, along with Emory researchers Francis Lee, Chris Ibegbu and Steven Nesheim, studied thymus dysfunction in 232 infants less than six years of age and postulated that certain strains of the AIDS virus not only deplete mature CD4+ and CD8+ T cells in infants, but also inhibit production of those cells by damaging the thymus. Thus, certain infants would exhibit particularly low levels of CD4+ and CD8+ T cells and would develop AIDS symptoms sooner. This tendency to deplete both types of T cells is in contrast to what occurs in most other HIV-infected children or adults; usually when the number of CD4+ T cells decreases, the number of CD8+ T cells increases.
The researchers estimate that this subgroup of HIV-infected infants with thymus dysfunction represents about 15 percent of all HIV-infected children. The Emory Pediatric Group, including Dr. Scott Clark and George Cotsonis from the Rollins School of Public Health, together with the CDC Perinatal Collaborative Transmission Study Group (PACTS), then extended these studies. They found that infection by certain strains of the AIDS virus acquired by the fetus during gestation caused the most severe, rapidly progressive disease and death, as compared to virus acquired at the time of delivery.
Thymic transplants may be particularly useful for preventing opportunistic infections in children with severe thymus dysfunction, says Dr. Nahmias. While most adult HIV patients have developed memory T-cells from past exposures to illnesses such as cytomegalovirus infection, allowing them to fight future infections even without thymic function, infants and children have not been exposed to most illnesses. Without thymic function they are not able to produce immune response to new antigens to fight opportunistic infections.
"We have proven that the methodology of thymic transplants is simple, requiring only one day of hospitalization and little use of potentially harmful drugs to prevent rejection of the graft as is necessary in bone marrow transplantation," Dr. Nahmias says. "No graft-vs-host rejection has occurred, and the main problem has been poor virus control and sometimes poor compliance. Together with Dr. Harold McClure and others at the Yerkes Primate Research Center we are continuing to improve our basic knowledge in an AIDS model in macaque monkeys as well as performing with Drs. Lee and Kourtis basic studies on the effect of different viral strains on the generation of T lymphocytes in a thymus culture system."
When Dr. Nahmias and his colleagues performed the first thymic transplant in 1993, he explains, only AZT and related drugs were being used in pediatric AIDS patients. Consentual prenatal testing, performed for the first time nationally in more than 95 percent of pregnant women at Atlanta's Grady Memorial Hospital by Michael Lindsay, M.D., Emory associate professor of obstetrics and gynecology, combined with pre- and postnatal antiretroviral therapy with AZT for HIV+ women, has dramatically lowered mother-infant transmission rates. Postnatal therapy for infected infants with combination therapy including protease inhibitors, has completely altered the effects of opportunistic infections in pediatric HIV-infected patients.
"Only a few years ago, it was much clearer that heroic measures were needed to save the lives of some HIV+ children," Dr. Nahmias points out. "Now that we are doing much better with treatment, the issue of which patients might benefit from thymus transplants or from any other methods to improve their effective host resistance mechanisms is much more complex.
"Although we believe our research is a significant step forward, we still need to determine which patients would actually benefit from transplants and in which ones antiretrovirals might be sufficient.
"We hope to learn more at the World AIDS Congress which patients, including adults, will need a combination of thymus transplant and drug therapy."
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