Researchers report finding a molecular key that could open the door to treating severe allergies and asthma with pills rather than injections.
Reporting in the British journal Nature, the scientists described the importance of finding a key that turns on the mechanisms responsible for the ailments.
By identifying molecular structures vital to the process by which the body's disease-fighting immune system responds with allergic reactions, the scientists are hopeful they can come up with novel strategies for dealing not only with allergy and asthma, which affect more than 50 million Americans, but also with such disorders as anaphylactic shock and autoimmune diseases.
In one study, Theodore Jardetzky, X-ray crystallographer and assistant professor of biochemistry, molecular biology and cell biology at Northwestern University in Evanston, Ill., and his team delved into the crystal structure of the complex called IGE-Fc/FceRia.
"By clarifying the atomic interactions that regulate the protein-protein interactions that mobilize and drive the body's immune responses, these new insights will hopefully lead to the development of novel immune-modulating drugs," the authors concluded.
In another investigation, Peter Sondermann of the Max-Planck-Institut f r Biochemie in Martinsried, Germany, and colleagues probed a related complex, the IgG1Fc fragment-FcRgIII.
Available relief now comes only in the form of drugs that treat symptoms, not the root of the sneezing, coughing and itching that are the hallmarks of allergies. For the most severe cases, injections are advised.
But now that the researchers have discovered how two vital molecules work together to bring on the distress, they said they have new tools -- and new hope -- for developing a new class of treatments that go after the source of the misery.
By thwarting the coupling of the all-important antibody and the cell receptor to which it attaches, researchers might be able to put the brakes on the release of chemicals that lead to the discomfort of allergies and the respiratory distress of asthma and anaphylactic shock. And the findings also could pave the way toward improved antibody-based treatments for autoimmune disorders and cancer, the study authors said.
Acting as lookouts for foreign invaders called antigens, antibodies neatly fit into their receptors on the surface of immune system cells, locking themselves in place for their watch. As soon as they detect the invasion of the potential troublemakers, the antibodies call the body's defenders to action. These immune cells then get to work, unleashing a barrage of defense mechanisms against the attackers.
In allergy and asthma, the allergen-recognizing antibody immunoglobin-E, or IgE, anchors itself in the receptor on the surface of mast cells, signaling them to produce histamine, leukotrienes, cytokines and other like substances that can bring on symptoms ranging from mildly irritating to severely debilitating.
"The antibody is the key that fits into the lock of the receptor on the mast cell," Jardetzky said. "When an allergen, say a molecule present in cat dander, attaches to the antibody, it provides the signal to turn the key. That is when the mast cell unleashes the chemicals that create such havoc in the body."
"With the antibody-receptor structure in hand, finding a new drug that can be taken orally to inhibit IgE is a definite possibility," said Jean-Pierre Kinet, professor of pathology at Harvard Medical School and director of the Laboratory of Allergy and Immunology at Beth Israel Deaconess Medical Center in Cambridge, Mass.
"Current anti-IgE therapies, used in the most severe cases of allergies and asthma, involve the injection of antibodies into the bloodstream once or twice a month. This is not a viable treatment for people who suffer, for example, from hay fever."
"The researchers went to the structure of the matter by imaging crystals of the molecular complex of IgE and its high-affinity receptor. The delicate task was performed with the aid of brilliant X-rays produced by the Advanced Photon Source synchrotron at Argonne National Laboratory in Illinois.
"In order to design drugs effectively, a chemist needs to know the structure and shape of the target molecules," Jardetzky said. "Our discovery provides a three-dimensional image of how the two molecules interact, showing where and how the antibody binds to the receptor. This is valuable information in the world of drug design."
The value comes in the knowledge of how the lock and key fit together. The scientists found the IgE antibody fits into two slots on the receptor and its shape make the antibody a better target than the receptor for drug treatments.
"Now that we know the structures of the antibody and receptor, we believe that it would be easier to find inhibitor molecules that attach to the antibody, thereby preventing the key from fitting into the lock," Jardetzky said.