Runny nose, anyone? Drippy eyes? Wheezy chest? Itchyskin?

Self-service pharmacies devote whole aisles full ofshelves to anti-allergy medicines, especially anti-histamines. For more serious complaints, doctors canprescribe any of 62 approved anti-histamines, fromActifed and Atarax to Tylenol and Vistaril.

All that these can promise is "temporary relief" (andpossible drowsiness), but they all warn that overdosing onthe active anti-histamine ingredient can harm patientswith glaucoma, ulcers or benign prostate disease. In veryyoung children, anti-histamine OD-ing may cause"hallucinations, convulsions and death."

Allergists know a lot about this sinister chemical enemy_ but not nearly enough.

Histamine pounces in response to an allergic antigen,which brings on such miseries as hayfever (rhinitis),asthma or atopic dermatitis. It dilates small blood vesselsand constricts smooth muscle (especially of the upperairways and digestive tract). Injury to the skin, even arough rubbing, sets off the classic "triple response": First,momentary whitening, as histamine rushes to the dermalscene; second, reddening; third, an itchy swelling.

Between engagements, histamine lurks in two types ofwhite blood cells: basophils and mast cells. When severeallergic reactions strike allergy-sensitive people, thesecells release histamine. They are the smoking gun;research allergists have spent years hunting for thetrigger.

Now, they've found it.

Today's Science carries an article titled, "MolecularIdentification of an IgE-Dependent Histamine-ReleasingFactor." Its senior author, immunologist LawrenceLichtenstein, directs the Asthma and Allergy Center atJohns Hopkins University in Baltimore.

Histamine: Homo Sapiens' Benefactor

"It's funny," Lichtenstein told BioWorld Today. "Thequestion everybody asks me is: `What use is histamine tosurvival of the human species?'" He explained: "You'vegot to go back a step and ask: `Why do we haveimmunoglobulin E? Why allergy?'" The reason, heanswers, is that histamine is part of a very effectiveimmune mechanism that kept man alive by getting rid ofparasites, worms mostly.

Lichtenstein went on to observe that "Parasites are not amajor problem in this country, so we are left with theresidual system, which has turned against us."

It turns in particular against the 25 percent of thepopulation that suffers from rhinitis, and the 5 to 10percent of asthma sufferers, Lichtenstein noted. Findingthe histamine-releasing factor (HRF), he suggested, "maylead to tests for predicting which people are at high riskfor severe allergic reactions, and perhaps to bettertreatment."

Actually, histamine strikes twice, immediately after theallergenic challenge, and again some hours later, as itpours out of its storage in the basophils and mast cells toinfiltrate target tissues in eyes, nose, bronchial tubes orskin.

This late-phase reaction, as it's called, presents twopuzzles: What triggers the delayed histamine onslaught,hours after the offending allergen has departed? And whydoes it torment only about half the population?

Hopkins allergist Susan MacDonald, first author of theScience paper, told BioWorld Today, "A decade ago, thenotional HRF molecule, then known only in its impureform, defined for the first time that immunoglobulin E,least common of all the four Ig classes, itself comes intwo heterogeneous denominations."

She explained: "While allergens, such as ragweed or catdander, are known to release the IgE-linked histamine onbasophils and mast cells, HRF triggers only basophilscoated with IgE+.

"That IgE+ molecule," MacDonald went on, "is found inabout 50 percent of the population, but it has nothing todo with a known allergen, such as ragweed. If a person isragweed-allergic, his basophils will discharge theirhistamine cargo when exposed to ragweed antigen.

"HRF," she continued, "only triggers basophils that haveIgE+ on them. That is linked to the late-phase reaction,which is caused by the more severe allergies, such aschronic asthmatic disease."

To isolate and sequence the IgE+-dependent HRF,MacDonald and her co-authors began with 50 liters of ahuman macrophage cell line, and eventually wound upsequencing a 23-kiloDalton protein. Running this througha GenBank library revealed striking homology to a humanp23, a gene abundantly expressed in tumor cells, but withno known function.

The recombinant p23 fusion protein her team expressedin E. coli caused basophils to release histamine fromeight IgE+ donor cells but not from the same number ofIgE- ones.

"It was a stroke of luck that Susan found it," Lichtensteinsaid. "We'd got a sequence, and it could have been that itdid not exist, and therefore we would have had to go afterit ourselves. In fact it did exist."

He believes that what he and his co-authors havediscovered, "is a mechanism for chronicity and severityof allergic diseases. It maintains the pro-inflammatory-mediated release of histamine after the allergen is gone."

The Hopkins allergist continued: "The main thing we'regoing after next is to determine why half of the peoplehave IgE+. We think that by having the HRF molecule,which we can now absorb in columns, we can make andpull out the IgE+ and see how it differs from normalIgE."

Wanted: A Biotech Firm To Help Get HRF Receptor

"Obviously," Lichtenstein pointed out, "HRF is not theinteresting molecule. It's the antagonist that's going to beinteresting."

He and his group have made progress, as yet unpublished,toward finding the HRF receptor. "We're not talkingabout it yet," he allowed, "because we haven'tdemonstrated it to be true. But we're not talking aboutanything particularly subtle. We believe HRF is acytokine, so it will have its receptor. We're veryinterested in getting it out."

To do so, Lichtenstein is talking to potential industrialpartners, "but we do not have anybody at the moment. Ibelieve it would have to be a biotech company," he said

ImmuLogic Pharmaceutical Corp. of Waltham, Mass.,defrayed the considerable cost of supplying 50 liters ofhuman macrophage culture for the Hopkins project. "Dr.Lichtenstein is a long-standing consultant to thecompany, and member of our global scientific advisoryboard," ImmuLogic's general counsel, Stacey Channingtold BioWorld Today." n

-- David N. Leff Science Editor

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

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