NIH study shows adult immune system rebuilds

You can teach old thymus gland new tricks

The thymus is functional and active well into adulthood, and this news holds great hope for HIV-infected patients who have seen their immune system beaten down by the virus.

While it’s commonly known that highly active antiretroviral therapy (HAART) can stop HIV from causing further damage, no one knew whe ther the existing damage could be reversed. A new study suggests this is possible.

"Say HIV destroys some of your T-cells that are programmed to fight a certain infection," says Richard Koup, MD, chief of infectious disease at the University of Texas Southwestern Medical Center in Dallas. "Then with HAART treatment, the thymus should be able to recreate those T-cells that were lost." Koup and Daniel C. Douek, MD, PhD, led a research team that measured a genetic by-product of T-cell development in blood samples from 10 HIV-infected and 30 uninfected people.

"If the thymus wasn’t active, you’d never be able to recreate those lost T-cells," Koup adds. "So it’s a very positive message for HIV patients, and it’s just one more reason for them to stay on their antiretrovirals and keep the virus down."

The study belies commonly held beliefs that the thymus gland loses its ability to regenerate cells in adults.

"Previously, the thought was that the thymus was active when you were young, but there is a dramatic decline in size and function with age," says Patricia D’Souza, PhD, senior scientist with the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH) in Bethesda, MD. NIH helped fund the study, which was published in Nature.1

"Think of T-cells as alphabet soup, and then some pathogen comes along and wipes out ABC, and we never knew if there was a way to replace them," D’Souza explains.

Tracking the origin of new T-cells

Researchers set out to determine whether naive T-cells found in adults were from the thymus or were pre-existing cells standing in the periphery, Koup says.

If the T-cells came from the thymus, then it would mean they were new and therefore recently produced by an adult’s thymus. The alternative would be that the cells arose through expansion of existing naive T-cells in the periphery.

However, determining whether the T-cells were new or existing was no easy feat.

"We had to develop an assay to tell us how the cells were coming out of the thymus," Koup says. "Other investigators had done the background work to address that question."

Before T-cells are released from the thymus, they generate circular fragments of DNA called T-cell receptor rearrangement excision circles (TRECs). Studies have shown that TRECs are stable and are not reproduced during subsequent cycles of cell division, so they’re present in naive T-cells but not in memory T-cells, which are the cloned descendants of cells that have already encountered a specific antigen.

"As T-cells encounter a pathogen, they respond and then become a memory cell, and then they either die or they enter a memory department," D’Souza explains. "What we didn’t know is if these T-cells lived so long if they were generated only in the young, or [because] they could regenerate as a person ages."

Koup’s team hypothesized that through the presence or absence of TRECs, they could identify which T-cells had recently left the thymus. TREC quantity declines significantly with age.

"As the cells divide with age, TRECs get diluted," D’Souza says. "The more TRECs you have, the younger the cell is."

Also, an analysis of blood samples from HIV-infected people showed that their TREC levels were significantly lower than TREC levels in blood of healthy people of the same age groups. All but one of the HIV-infected individuals showed a rapid and sustained increase in TRECs after receiving HAART.

Children produce more new T-cells

The study showed that young people have many more of the TREC markers than older people, but even in people over age 70 there still were markers indicating freshly minted T-cells. For instance, children have 10 times the output from their thymus as do adults, Koup says.

"If you consider the rate of production of T-cells from the thymus, it’s a slow trickle in an adult, and in a child it’s a wide-open faucet," he adds.

This means children who have HIV should be able to recover their immune system potency much faster than adults. "With the treatment with HAART, what we hope is that the child’s immune system will be reconstituted much more rapidly, and if we can keep the virus suppressed, then it might lead to a much more normal life for that child," Koup says.

But this discovery still holds promise for adults.

"The first message is, the thymus is active well into retirement age, and now we have a way of measuring thymic output," D’Souza says.

The research could lead to therapies that pump up the thymus’ function and help it pump out more new T-cells in adults, as well. "One of our hopes is to measure thymus output, and that we can come up with therapies to increase the output of the thymus," Koup says.

These therapies could help HIV-infected patients and cancer patients after chemotherapy treatment. "Patients undergoing bone marrow transplants for whatever reason could benefit, so this is another example of how research in one area could benefit patients who have many different diseases," Koup adds.

In summary, the study’s findings were the following:

    • Thymic activity becomes less efficient as people age, and therapies that directly improve thymic function in adults may increase the rate of immune reconstitution after HAART.

    • Changes in TREC levels occur early in HAART treatment and are indicative of thymic potential for reconstitution of naive T-cells.

    • Thymic function in HIV-infected adults may be suppressed, and it can be improved by the reduction of viral load.

Reference

    1. Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396:690-695.