In the great game played by the body's immune defense system,eosinophils are on the minor-league team. But those white blood cellshave a lot to answer for.
Sure, eosinophils play host defense against invading intestinalparasites, such as nematodes (round worms), blood flukes andschistosomes. However, on the offensive side, they are also allegedco-perpetrators of asthma, hay fever, eczema and other inflammatorydiseases.
"It is thought," said immunologist Charles Mackay of LeukoCyte Inc.in Cambridge, Mass., "that the eosinophil, a granulocyte that is a verytoxic type of leukocyte, releases substances that damage or destroythe lung or airway epithelium."
Eosinophils rush to the scene of an inflammatory event, guided byseeing-eye molecules called chemokines, which the inflamed cellssecrete.
"There are nearly a score of these special-purpose cytokines,"Mackay explained, "which lure immune-defense cells into aparticular tissue or particular site to repel antigenic invaders. Theway the cell moves from the blood across the endothelium and intothe tissue is called chemotaxis. That is, the chemokines act aschemical attractants."
A recently discovered chemokine called eotaxin binds to its ownspecific receptor on the surface of eosinophils, and attracts them tothe airway target area.
Using a partial mouse cDNA probe, the company and its sponsoredacademic researchers discovered and cloned the human form ofeotaxin, said Mackay, who is director of immunology at LeukoCyte.The scientists also found eosinophils and eotaxin abundantlyexpressed in a human nasal polyp.
Mackay told BioWorld Today: "The reason we are so interested ineotaxin is that this could be the molecular mechanism for recruitingeosinophils to the airways. And it is our feeling that it is aninappropriate recruitment."
He is senior author of a paper in the February issue of The Journal ofClinical Investigation, titled: "Cloning of the Human EosinophilChemoattractant, Eotaxin."
Mackay observed: "We think it very important to develop a potentclass of antagonists to the eotaxin binding to its receptor on theeosinophils. That way, we could inhibit the recruitment of eosinophilsfrom the blood, in asthmatics."
He sees this type of therapy "as something that would be novel, thatcould replace or supplement current therapies for asthma, such ascorticosteroids."
Eotaxin Receptor Also Drawing Interest
LeukoCyte's chairman and CEO, molecular pharmacologistChristopher Mirabelli, stated his company's interest "not only in theeotaxin ligand but in its receptor." He told BioWorld Today: "Weended up serendipitously identifying, cloning and characterizingboth."
Mirabelli continued: "The fact that this eotaxin receptor is lookingmore and more like the predominant chemotactic receptor oneosinophils suggests for us that it is a very interesting target for anumber of allergic hypersensitivity diseases, certainly includingasthma."
The company has submitted patent applications covering botheotaxin and its receptor. "In addition," Mirabelli observed, "we haverelationships with a number of academic investigators working in thisarea."
One such is immunologist and geneticist Jose-Carlos Gutierrez-Ramos of Harvard Medical School's Center for Blood Research Inc.A co-author of Mackay's paper, his research is partly funded byLeukoCyte.
Gutierrez-Ramos explained to BioWorld Today that in asthma,eosinophils mediate the late-phase reaction of airway and lungtissues, hours or days after exposure to allergens, whereas the acuteasthmatic attack, which occurs within minutes, results fromImmunoglobulin-E unleashing mast cells against the airway epithelia.(See BioWorld Today, Feb. 14, 1996, p. 1.)
"When you target your efforts to prevent eosinophilia in the lung," heobserved, "you are spoiling this fertile soil for the attack. We havevery good mouse models of asthma in our laboratory, in which wehave reduced the eosinophils enormously."
Gutierrez-Ramos concluded: "These eotaxin-like chemokines are sospecific in their activity, attaching to eosinophils, that they representa really interesting target for therapeutics."
"Chemokines are relatively small molecules," said Mirabelli, "about70 amino acids long, which also makes them interesting as a drug-discovery target. That size," he observed, "suggests that they mayhave enough information and potency to provide a powerfulantagonist activity." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.