A congeries of cell-to-cell messengers have become householdwords among immunotherapists. These cytokines _ interferon, theinterleukins, tumor necrosis factor, colony-stimulating factors, toname a few _ spring into action when alerted by foreign antigens.
Signals from cytokines activate the body's immune defenses, inparticular certain front-line white blood cells, neutrophils andmacrophages. Both of these search-and-destroy cells scavenge debris(such as dead bacteria) from the bloodstream; each also performsother vital immune-system missions.
To give these cells a nudge or guiding push toward the scene ofantigenic invasion, certain cytokines deploy chemotaxis _unidirectional chemical attractants. Two kinds of these chemokines(chemotactic cytokines) are known to molecular immunologists:cysteine-cysteine (CC) chemokines turn on macrophages; CXCs turnon neutrophils.
Now, in the current issue of Science, dated Nov. 25, scientists at theDNAX Research Institute of Cellular and Molecular Biology in PaloAlto, Calif., report discovery of "Lymphotactin: A cytokine thatrepresents a new class of chemokine."
DNAX immunologist Albert Zlotnik, the paper's principal author,told BioWorld Today, "What we know so far is that lymphotactinseems to be a potent chemoattractant for lymphocytes." These are theB and T cells that mediate the specificity of immune responses.
Molecular Police Direct Cellular Traffic
"If one lymphocyte somewhere makes lymphotactin," Zlotnikexplained, "this would result in other lymphocytes coming in _perhaps like calling the 911 number." He also likened chemokines totraffic cops, signalling the directed movement of white blood cells.""It is also possible, he added, "that they are regulating the variousfunctions of those cells, but we don't know yet."
Zlotnik and his collaborators had previously found that "if weactivated mouse progenitor T cells in a certain way, they wouldproduce high titers of gamma interferon, interleukin-2 andgranulocyte-macrophage colony-stimulating factor. The real question was: Could they also be makingsomething new?"
Angling for an answer, he continued, "we went fishing in a lake thatnobody had ever fished before _ screening a cDNA library of thoseprogenitor T cells, for starters _ to see whether we could find a newand abundant source of cytokines."
That was how they landed lymphotactin, possibly representing, athird class of chemokines, but with two fewer cysteines than the twoknown molecules.
To demonstrate the lymphotactin's ability to lure and impel itslymphocyte target along a chemical gradient, the researchers placedtheir recombinant chemokine in one of two chambers, separated by afilter. "We put several lymphocyte populations into the otherchamber, and they all migrated toward the filter, a little as if bymagnetism," Zlotnik said.
Actually, he explained, what drives chemotactic cytokines "is asignal, a mediator. One cell makes it. It then binds to another cellthat has to have a receptor specific to it. That tells the cell thatreceives the signal where to go, to start moving in a certaindirection."
The DNAX team performed all this molecular biology in vitro withmouse cells, and localized the lymphotactin gene to murinechromosome one. More recently, Zlotnik disclosed, "We have founda human homolog to the mouse gene. Suffice it to say, we now havethe human molecule."
In "projects down the road," he said, "we're going to becharacterizing the in vivo effects of this human chemokine. "If thisreally has the same effects in vivo that the mouse one had in vitro,"Zlotnik suggested, "that is, if it's chemotactic for lymphocytes, onecould imagine some pathology where you might want to bringlymphocytes to a particular place in the body." He noted that"lymphotactin affects preferentially activated CD8+ T lymphocytes."
Therapeutic, Intellectual Potential
Molecular immunologist Mark Moore, a senior scientist atGenentech Inc., in South San Francisco, acclaims Zlotnik's work as"a major discovery." Moore told BioWorld Today: "It's really atremendous result. This discovery, and the whole chemokine field ingeneral, has tremendous potential, therapeutic as well as intellectual,because the whole mechanism of how lymphocytes migrate to thesite of inflammation is of tremendous importance, particularly inrheumatoid arthritis, and other types of inflammatory andautoimmune diseases." He added, "If we can learn how to regulatethe migration ability, we might find some way to break this cascadephysically."
Moore's lab at Genentech, he explained, "is using molecular biologyin gene-knockout mice to really dissect the immune system, and tryto determine what role these chemokine molecules have.
"Their specificity," Moore continued, " is very exciting. With the IL-8 receptor in our mice, we find it's exquisitely specific forneutrophils. As Albert [Zlotnik] is expanding this new chemokine, aswe find more and more of them with higher degrees of specificity, itreally should help put together a very nice picture of how thelymphocytes migrate to various organs throughout development, andalso throughout infectious diseases." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.