An Anglo-Australian team of molecular geneticists has set out toclimb a genomic Mt. Everest. Upon reaching its cloud-covered peak,they hope to unfurl a banner identifying the principal genes forasthma.
Right now, the party has just moved out of its base camp, and sentback a status report, which appears in today's Nature. Its title: "Agenome-wide search for quantitative trait loci underlying asthma."
The team's leader, and senior author of the paper in Nature, is Britishgeneticist William Cookson. "Some of asthma's genetic effects,"Cookson told BioWorld Today, "affect one's ability to becomeallergic; others, the ability of one's airways to become inflamed."
Earlier climbers, Cookson said, "have identified a number of thecomplex genetic effects on asthma, particularly on humanchromosomes 11 and 5." These two previous discoveries, heobserved, "had to do with allergy."
"But it's obvious," he continued, "that these genes did not explain thewhole genetic predisposition to asthma, so we set out to lookcomprehensively through all of the genome, and try to identify mostof the major genes that influence the syndrome. That's what'sreported in Nature."
They explored six genomic regions that contribute to the highlypolygenic asthma phenotype. "Five of them," Cookson said, "onchromosomes 4, 6, 7, 13 and 16, are new.
"The next thing to do," he continued, "is to find the genesthemselves. This is an enormous amount of work, which willprobably require industrial-scale gene searching _ positional cloning.It's already under way here in Britain." Cookson heads the asthmagenetics group at Oxford University's Wellcome Trust Center forHuman Genetic Diseases.
Of late, his gene searchers have scaled new heights in asthma'sgenomic foothills. "We've made quite a deal of progress," Cooksonsaid, "with mapping four of the loci. But I think the thing to say isthat there are still three or four years' work before we come up withthe genes."
The Australian contingent blazed the uphill trail by collecting andstudying 203 offspring in 80 asthma-prone families in the town ofBusselton, at the extreme southwestern corner of the continent, about150 miles due south of Perth.
"There's a lot of asthma in the Australian environment," Cooksonobserved. "It affects 15 percent of Australian children, about thesame proportion as the one in seven asthmatic children in the U.K.And in Britain," he added, "as well as the U.S., asthma's incidence iscreeping up."
Rats, Guinea Pigs, Monkeys Fetter TNF
Strangulation accounts for the spasmodic wheezing, coughing andgasping for breath that mark an asthmatic attack. It reflects the literalchoking of airways in the lungs and bronchial tubes.
In crime movies, the victim is usually smothered by a pillow presseddown on the face, or by a scarf, wire or bare hands around the neck.
In asthma, an inflammatory process cuts off breathing, by causing theairway walls to swell, and mucus to plug their passages. What startsthis airway contraction hyper-responsiveness process may be anallergen, such as pollen or house dust. What makes some peoplesusceptible to such attacks has a large hereditary component.
But whether from "bad" genes or dusty environment, what triggersthe actual autoimmune reaction is still subject to research.
One recent clue fingers an aggressive cytokine, tumor necrosis factor(TNF) as the immediate perpetrator of an asthmatic attack. TNF'slatest indictment comes in the August issue of the Journal ofPharmacology and Experimental Therapeutics, where researcherLouis Renzetti and his team at Hoffman-La Roche Inc., of Nutley,N.J. report: "Pharmacological evidence for tumor necrosis factor as amediator of allergic inflammation in the airways."
When a body's immune defenses encounter an allergenic spasmogen,as in dust or pollen, it mobilizes a class of antibody calledImmunoglobulin E (IgE) to take countermeasures. These encompassrelease of a complex cascade of proinflammatory cytokines, of whichthe first and foremost is TNF.
Renzetti told BioWorld Today, "TNF is an early-response cytokine.Besides its own direct biological actions _ and more importantly _TNF amplifies the effects of the other cytokines, making them evenworse." Then, in a comment that harks back to Cookson's genomicascent, he observed: "The TNF gene locus is believed to correlatewith symptoms of asthma. Its genes cluster on chromosome 6, wherepeople are trying to identify the asthma gene."
Scientists at F. Hoffmann-La Roche AG in Basel, Switzerland, havedeveloped a synthetic recombinant TNF blocker, which they call Ro45-2081. To do so, Renzetti recounted, "They took two human TNFreceptor molecules, placed them on human immunoglobulin G., andusing recombinant-DNA technology, make them into apharmacological tool to block TNF."
Then Renzetti and his co-authors at Roche'sinflammation/autoimmune diseases therapeutic area in Nutley testedthe compound in guinea pigs, rats and more recently in cynomolgusmonkeys. "It abolished the airway hyper-responsiveness," Renzettisaid, "triggered by challenge with potent spasmogenic allergens."
It did so, he explained, "by abolishing TNF levels, which is whatyou'd hope, without any effect on other cytokines, such as interferonand interleukin-4."
Renzetti plans to present his latest Ro 45-2081 experimental resultsto a joint meeting of the Academy of Allergy, Asthma andImmunology and the Association of American Immunologists, in SanFrancisco this February.
Human volunteers who inhale TNF also develop airway hyper-responsiveness. Renzetti is not yet ready to say how the Ro 45-2081molecule might affect this effect in humans.
"The research is still early," Roche spokeswoman, Darien Wilsontold BioWorld Today. "It's research that we have to presentinternally to people at Roche, to see if we're going to move forwardwith it as a drug-development compound. It's not at that stage yet,"she continued, "but it certainly gives us more grounds to go to ourdevelopment board and see if it's something that will progress astreatment for asthma."
Asthma being only one of many autoimmune diseases, Renzetti andhis co-authors find that "TNF is certainly a valid target for testing Ro45-2081 in multiple sclerosis and rheumatoid arthritis, among otherentities, on which they also are working. n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.