David N. Leff
All over the industrialized world, asthma is dramatically on the rise - and nobody knows why.
"In the U.S. alone," observed immunologist Marsha Wills-Karp, "15 to 16 million people - 8 percent of the population - suffer from asthma. In countries like Great Britain and Australia, she added, the percentage of affected people runs "as high as 10 to 12 percent."
To account for this mysterious upsurge, Wills-Karp said, "A lot of current ideas are being tossed around. The first one sort of started in the 1970s, when the energy crisis promoted devices to weather-proof and tighten up homes. So, occupants got more exposed to interior allergens - dust mites in particular, and pets in general. But the problem with that idea is that this happened a long time ago, and the growing asthma epidemic still persists."
Wills-Karp is an associate professor of physiology in the Johns Hopkins School of Public Health, in Baltimore.
"The explanation that seems to hold up most," she said, "is associated with Westernized society. For example, East and West Germany, before they united, had the same pollution exposure and genetic background, but very different modes of living. The Western part was more affluent. So, its high-fat diet and sedentary lifestyle somehow impacted on this, but we don't have the slightest clues - no mechanistic data - to support how that's affecting asthma. I think it's intriguing, but it will be difficult to prove."
A tendency to asthma is known to be partially inherited, she said, "but that doesn't explain the increase over time, because the genetic pool hasn't changed that much."
Wills-Karp is one of many who are endeavoring to get to the bottom of asthma's etiology and course. She is first author of a paper in today's Science, dated Dec. 18, 1998, bearing the title "Interleukin-13: Central mediator of allergic asthma."
Back-to-back with her article is a strikingly similar report titled "Requirement for IL-13 independently of IL-4 in experimental asthma." Its senior author is pulmonologist David Corry, at the University of California, San Francisco (UCSF). Commenting on both papers is a journal editorial, "Interleukin-13's key role in asthma shown."
IL-13 is one of many cytokines - messenger molecules that help coordinate immune defenses - sent out by certain helper T cells to the scene of an allergenic attack on the body's airways. Its constant sidekick cytokine is IL-4, and the two buddies share a common receptor, which honchos their effects.
"Their beneficial actions in normal, non-asthmatic people," Wills-Karp told BioWorld Today, "are to dampen inflammation. So, in the case of a viral infection, say, they would come in and turn off the responses to prevent damage to the tissues. In normal individuals, our immune system knows that we've been exposed to those allergens that we all inhale, but we develop tolerance to them. Asthmatics, for some reason, respond by bringing in and activating these helper T cells, which then release cytokines, including IL-13 and IL-4."
Vaccinating Mice Against Asthma
Wills-Karp and her co-authors enlisted a strain of wild-type mice spontaneously susceptible to contracting asthma in the presence of an allergen.
"We sensitized these animals," she recounted, "to ovalbumin, a foreign allergenic protein. After a preliminary injection in the gut, they subsequently inhaled it direct to the lungs. A few days later, the mice had an immune response, characterized by an influx of those helper T cells, which released a swarm of cytokines, mainly IL-4 and IL-13. These two triggered the murine equivalent of human asthma."
In those experiments, the Hopkins co-authors followed up with a soluble IL-13 receptor fragment that binds only IL-13, not IL- 4. "And when we gave that," Wills-Karp said, "we were able to eliminate the allergic response that the animals normally developed. That result suggested to us that IL-13, not IL-4, mediates the response."
Very similar experiments by UCSF's David Corry suggested the same conclusion - in spades.
"Our two papers say very much the same thing," Corry told BioWorld Today. "Both implicate and demonstrate the very potent role of this orphan cytokine, interleukin-13, which everybody knew was there, but nobody knew what it did. We looked at all three molecules - IL-13, IL-4 and their mutual receptor - at the same time, to try to understand how they all fit together. We have shown that in a mouse disease which looks very much like human asthma, IL-13 is really a bad player. It's a very important molecule, which cannot be ignored. And it's a very potent target for therapeutic intervention in asthma."
Both groups dosed their mice with the IL-13-neutralizing soluble receptor fragment, which they obtained from Debra Donaldson of Genetics Institute [GI], in Cambridge, Mass. She is senior author of the Hopkins paper in Science.
Will IL-13 Prove A Therapeutic Lucky Number?
"The company that both our groups collaborated with on these studies," Wills-Karp pointed out, "is [GI]. To be honest, we would not have been able to separate IL-4 from IL-13 without GI having cloned the unique IL-13 receptor."
Corry said another company "with which we cooperate has given a different soluble human IL-4 receptor to humans with asthma in a Phase I trial. It appeared to be very effective."
Researchers have not proven their case in humans, he noted. "That's going to be up to other people," he said. "Also, we have great hopes that this is going to be a 'magic bullet.' But, please keep in mind that anytime you start to manipulate the immune system, you run into very serious side effects. Say you started giving a systemic drug that blocked IL-4/13 receptor signaling. Say it worked great and wiped out asthma. If you give that helter-skelter to people, what you'll do is block all immune responses coming through that receptor. So, I would imagine that local or aerosol administration to the lung is the route these things would be given by."
Wills-Karp concluded: "You have to be cautious about extrapolating from the murine to the human. Even if this reagent that they're working on at GI doesn't pan out, or has side effects, we will still gain a lot of information from that to dissect the asthma mechanism a little bit further." n