What's wrong with this "dictionary" definition?

thy-mus (thi' mas) n., a small glandular organ situated behind the top of the breastbone, consisting mainly of lymphatic tissue, and serving as the site of T cell differentiation. The thymus increases gradually in size and activity during infancy, then stabilizes until puberty. Thereafter, it undergoes involution, and much of its lymphoid tissue is replaced by fat. It is necessary in early life for the normal development of immunological function, but thymus activity is virtually depleted by the third decade.

That dogma, which holds that the thymus gland arms the young with immune T cells, but leaves the middle aged and elderly defenseless, raised viral immunologist Richard Koup's eyebrows. "The fact [is] that in HIV infection," he told BioWorld Today, "when we treat patients with highly active antiretroviral therapy [HAART], we're seeing increases in the naïve T cells. It just seemed reasonable that maybe the adult thymus was still functioning."

The thymus churns out T lymphocytes, the body's frontline defense against infection. HIV infection destroys those cells, opening the way to AIDS.

A rookie T cell, recruited from the bone marrow, makes its way to the thymus for boot-camp training. Then, it exits that organ and reports to the bloodstream. Until it has actually encountered the antigenic profile of a prospective enemy antigen, that T cell is rightly called naïve. But, once it has memorized the molecular contours of its blood-feud foe in question, the T lymphocyte can join the ranks of an estimated 99,999,999 other thymus-graduate memory T cells, and take up guard duty against a possible attack by its specific antigenic target.

Oldsters Displayed Unexpected Thymic Potency

Like virginal antibodies, naïve T cells go through astronomically complex genetic maneuvers before they win their stripes as battle-ready memory cells.

Koup explained: "The T cell receptor gene is extremely diverse, so it can produce all of the T cell receptors to identify any pathogen. But each T cell has to rearrange that gene such that it expresses a single receptor with a single specificity.

"During that process, large portions of the DNA are cleaved out, while plasmid-like DNA circles are produced, which the cell has to retain. These T-cell receptor rearrangement excision circles [TRECs], appear to be garbage, basically. The T cell doesn't need them any more, but has no way of getting rid of them except to pass them on to its progeny."

However, these apparently useless TRECs provided Koup with a way to show that, despite common wisdom, the thymus can overcome its age-imposed withering away of T-cell immunity.

He is senior author of an article in today's issue of Nature, dated Dec. 17, 1998, titled "Changes in thymic function with age and during the treatment of HIV infection."

"Our first goal," he said, "was to develop an assay for measuring the T cell output of the thymus. To do that, we looked for the TRECs, those byproducts of the T cell receptor gene rearrangement process. Then we followed the dilution of them as T cells divided and proliferated after leaving the thymus. What we did then was to see if the TREC-based assay we had developed made sense, considering what we know about the adult thymus.

"So, we measured the amount of these DNA circles in young people versus people as old as 73, and found that their number went down in both," Koup said. "But we also found that in older people who had had their thymuses removed, the TRECs went down even further. This indicated that even the low level of those circles that most adults have is being maintained by output from the thymus. It was the removal of the thymus that caused the decrease."

Such thymus-ablated patients serve as in vivo models, adding evidence in support of Koup's hypothesis.

"In most individuals," he said, "removal of the gland affects the subsequent immune system. But what we don't know is whether those individuals then go on to get cancer or HIV infection or autoimmune disease and are treated with chemotherapy, which depletes their blood-borne T cells. The unanswered question is: Does the removal of that organ then affect their ability to reconstitute their immune system? Our recent data would suggest that maybe it would be best to leave as much of the thymus as possible.

"Those data conclude," he said, "that the adult thymus is still functioning to produce new T cells -- that, in patients who are infected with HIV, who then undergo treatment with HAART, and where we see an increase in naïve T cells, that increase is not from just peripheral expansion of whatever remaining naïve T cells there were in the blood after HIV infection, but is contributed to by production of new T cells from the thymus. Blood samples from HIV-infected people showed significantly lower TREC levels than in age-matched healthy individuals. But, after going on the HAART regimen, nine of 10 showed rapid and sustained increase in TRECs.

Virus And Thymus In Ding-Dong Battle

"This indicates," Koup said, "that, given enough time and adequate viral suppression, we would expect that the adult immune system could reconstitute itself. That is, thymic activity goes down when viral load goes up. If you shut down viral load, you allow the immune system to recover.

"Just like in HIV infection, where the virus destroys peripheral T cells, the chemotherapy that we give for cancer destroys peripheral T cells," he added. "So, knowing now that the adult thymus is functioning, and can help reconstitute the immune system after chemotherapy, is also important in terms of predicting how well an individual is going to do, based upon his or her age, after receiving chemotherapy.

"Ultimately," he concluded, "the goal would be to increase the output of the thymus. And we don't have a way of doing that yet, but as we now have an assay to measure thymus output, then we should be able to develop those therapies. That's one of the things we're working on now." *

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