Young T lymphocytes, born in the bone marrow, make their way tothe thymus for two kinds of training:

First, they learn to spot, and stop, future foreign infiltrators, such asinfectious pathogens and rogue cancer cells. These enemy-alienproteins carry identification tags in the form of antigens, by which theT cells will recognize and kill them.

Second, the rookie lymphocytes must pass a course in tolerance, howto tell antigenic friend from foe, protein self from non-self. T cellsthat fail this test may bring down friendly fire on "self" proteins,causing autoimmune diseases in their own body.

The thymus is a harsh boot camp. T cell trainees that fail to make thegrade are terminated with extreme prejudice, by apoptosis _programmed cell death.

Death can also threaten the entire body in the prime of life, wheninvaders such as the AIDS virus or cancers overwhelm the immunesystem's T-lymphocyte immune arm. And with advancing years,some T cell clones forget their vows of tolerance, to protect "self"antigens in the body from friendly fire. Such autoimmune diseases asmultiple sclerosis, rheumatoid arthritis, amyotrophic lateral sclerosisand systemic lupus are commonest among people at or past middleage.

Rejuvention of the dwindling, post-adolescence thymus gland, manyresearchers believe, might strengthen that organ's output of T cellstrained to repel invaders and tolerate innocent "self" bystanders.

At the Bristol-Myers Squibb Pharmaceutical Research Institute, inSeattle, molecular geneticist Christopher Clegg and his co-workershave found a back-up system in the body that can recruit battalions ofbattle-ready T cells to fill gaps in the immune system's lymphocyteranks.

The recruiting sergeant for this mobilization is a molecule calledoncostatin M. It belongs to the interleukin-6 subfamily of cytokinesexpressed by blood-forming tissues and cells.

No T Cell Monopoly For Thymus

Clegg is first author of a paper in today's Nature titled: "Regulationof an extrathymic T-cell development pathway by oncostatin M."

Oncostatin M [OM], Clegg told BioWorld Today, was discovered athis research facility in Seattle a decade ago. "It is produced," he said,"in the thymus, in the bone marrow and by activated T cells andmacrophages."

Now, Clegg and his co-authors report that they have constructedtransgenic mice that express OM genes in their lymph nodes. After16 weeks, those nodes contained 500 times more mature andimmature T cells than did those of controls.

Besides the thymus, their front-line primary element, the immunedefenses deploy a body-wide secondary network of command postsand communications lines called the lymphatic system. Its peripheraloutposts range from the spleen to bone marrow to tonsils andadenoids, all interconnected by a meshwork of lymph nodes.

"Next we took bone marrow from the transgenic animals," Cleggcontinued, "and injected it into lethally irradiated, marrow-dead nudemice. They started to produce lymphoid cells, and we saw the same Tcell output phenomenon as in the transgenics."

To test the efficiency of those T cells, they seeded mouse melanomatumors into OM-secreting mice and controls. After 10 days, theformer had only 10 percent as much tumor burden as did the latter.

Another experiment showed that thymectomized mice made T cellsin their lymph nodes, thanks to native OM, even without benefit ofOM gene therapy.

Clegg said he foresees a clinical role for OM in restoringimmunodeficiency in humans, particularly the aged. "We think itcould be used to increase the number of naive T cells _ trained butnot yet antigen-challenged _ over time."

Having demonstrated OM's performance in transgenic mice, he said"our next step will be in primates infected with simianimmunodeficiency virus, as an HIV model, and for AIDS-associatedopportunistic infections."

Besides AIDS, Clegg said he sees a future for OM in bone-marrowtransplantation. "After such a procedure it's over a year before thepatient regains the T cell immunity response," he said. "OM mightaccelerate that recovery."

He went on: "People receiving cancer chemotherapy have depressedimmune systems, because the drugs kill off numbers of those Tlymphocytes. If you could boost the population of T cells insomebody who has received a round of chemotherapy, it wouldshorten hospital stays."

Spleen Also Pinch-Hits As T-Cell Source

At the University of Maryland, immunologist Garnett Kelsoe isexploring the basic-science mechanism by which the spleen churnsout T cells for emergencies, giving the thymus the run-around. Hispaper, also in today's Nature, bears the title: "Alternative pathwaysfor the selection of antigen-specific peripheral T cells."

As Kelsoe told BioWorld Today, his paper focuses on the apoptoticpathway of death, hitherto known to exist only in the thymus.

"In the spleen," he said, "antigen-specific B cells encounter antigen-specific T cells. We show for the first time that they intenselyproliferate, creating a big ball of activated cells _ the germinalcenter. In this environment," Kelsoe observed, "there's a lot of neatstuff going on _ as we say technically.

"What our paper demonstrates," he said, "is that there is a great dealof selective T cell death in the germinal center, which mimics thepathway of immature cell death in the thymus."

He concluded: "These death pathways are put in place as a fail-safedevice to prevent the escape of autoreactive lymphocyte clones,which instigate autoimmunity." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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