3 July 2002 10:00 GMT

by Bea Perks, BioMedNet News

Immunologists hunting for the cause of asthma could be looking in the wrong place, suggests Manel Jordana, an immunologist at McMaster University in Hamilton, Ontario. There has been enormous interest recently in the role of a group of lymphocytes called Th2 cells, but this has overshadowed possible roles played by other cell types, including those of the innate immune response, he says.

Jordana, professor of the health sciences at McMaster, calls for a fresh perspective, urging researchers to go right back to the very beginning of the immune response, at the point where an allergen first meets the asthmatic immune system.

Asthmatics, compared with non-asthmatics, have increased numbers of Th2 cells together with increased levels of the cytokines that they produce. While immunologists fail to agree on an underlying reason for this, they agree that the cells and their cytokines are central to asthma pathogenesis.

To date, says Jordana, nobody has sought to link the observation to the agents that actually trigger asthma - airborne allergens, such as dust mite allergens and pollen.

Jordana calls for the current research focus on T cells and their cytokines to be shifted towards cells of the innate immune response. These are the cells that make the first contact with aeroallergens, he notes: the epithelial cells that line the airways, and the alveolar macrophages that patrol the surrounding tissue.

Both these cell types respond to external stimuli by producing a cytokine called granulocyte-macrophage colony-stimulating factor (GM-CSF), which has long been considered a mediator of asthma.

Jordana now suggests that GM-CSF is not just a mediator but a "major instructive signal" in determining the body's response to airborne allergens.

He supports his hypothesis with recent discoveries that a polymorphism in the gene for GM-CSF has been described in an asthmatic population; that GM-CSF levels are unusually high in the airways of patients with asthma; and that introducing GM-CSF into the airways of lab mice provokes an inflammatory response to otherwise innocuous antigens.

GM-CSF is also known to induce the proliferation, activation and maturation of dendritic cells, the most potent professional antigen-presenting cells in the immune system. Importantly, notes Jordana, GM-CSF-stimulated dendritic cells have been shown, at least in mice, to elicit Th2-type immune responses.

Jordana and his colleagues make the case for GM-CSF in an Opinion article in the August issue of Trends in Immunology.

"We believe that the potentially important role of GM-CSF in the pathogenesis of asthma has been largely overshadowed by its Th2-affiliated cousins," the authors note.

Although GM-CSF has long been considered an asthma mediator, agrees British asthma expert Peter Barnes, Jordana succeeds in emphasizing "the important role that it may have in tipping the balance in favor of Th2 cells."

The principal treatment for asthma, corticosteroids, are very effective at switching off the GM-CSF gene, says Barnes, a consultant in respiratory medicine at the Royal Brompton Hospital in London. This action, he notes, may contribute to their efficacy in controlling asthma.

"Specifically blocking GM-CSF using blocking antibodies, muteins [mutated recombinant proteins], or receptor antagonists is a possible strategy for treating asthma," he told BioMedNet News. "But is likely to be too specific as it would not block the many other cytokines that may contribute to the inflammatory response that are inhibited by corticosteroids."

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Regulatory T cells and allergic asthma
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