Irritant breakthrough in understanding allergies

[Althalus]

A UK team has discovered how antibodies involved in causing allergies stick to key cells, called mast cells, causing them to continually release irritants. The work could lead to new drugs to "switch off" hayfever.

Most drugs on the market simply subdue allergy symptoms. Medicines like antihistamines can fight off red eyes and runny noses temporarily. But they can have bad side-effects and the more you use, the higher doses you need to get the same effect.

Researchers have long been searching for ways to hit the allergic system earlier in the game, but they have been hampered by not knowing exactly why allergic reactions can be so severe and long-lasting.

Most of the irritating effects are caused by antibodies called IgE. Brian Sutton at King's College London and colleagues have found that the Y-shaped antibody is bent back on itself. When the antibody attaches to a mast cell, it unbends by about 90 degrees, somehow securing itself in place.

A drug that locks the antibodies into their bent shape would stop them binding to mast cells, or even pop them off.

But not all allergies are triggered exclusively by IgE. "Anti-IgEs are going to be useful, but not the cure to everything," cautions Hasan Arshad of the David Hide Asthma and Allergy Research Centre on the Isle of Wight

Existing drugs

IgE antibodies are present in everyone's immune system, though an allergy-prone person can have thousands of times more than a healthy person. The antibodies are thought to have evolved as a protection mechanism against parasites. But some have developed other sensitivities, causing some people's immune systems to run amok in the face of innocent invaders like peanuts or pollen.

The Y-shaped IgE antibodies attach themselves to hosts called mast cells. When their upper arms detect an allergen, they signal the mast cell to release irritants, such as histamines. Most antibodies stick on to their hosts for a few minutes while on the attack, but researchers now understand how IgE antibodies can stick to mast cells for weeks.

Custom-designing a drug to specifically alter the shape of a molecule has never been done before so it could be a tricky enterprise. But, surprisingly, a drug designed by the American company Genentech might already do the trick.

Their compound, Xolair, is known to interfere with IgE - but it is not known exactly how it does it. "This could be the mechanism by which it works," says Sutton.

Xolair has been through promising clinical trials, but because the drug is a large molecule it has to be administered by injection and is very expensive. Sutton hopes his team's new understanding of IgE means researchers will be able to design a small-molecule drug that can do the same thing, but be popped as a pill.

A few rounds of such a drug might even make someone less inclined to allergies. Previous studies have shown that when IgE antibodies stop pestering mast cells, the mast cells stop growing receptors for them.

Journal reference: Nature Immunology (DOI:10.1038/ni811 (http://dx.doi.org/10.1038/ni811)