Experimental Therapy Stops Allergic Reactions in Mice

Scientists supported by the National Institute of Allergy and Infectious Diseases (NIAID) have devised a new, experimental approach to treating allergic diseases. In mice, the scientists used a genetically engineered molecule to connect two receptors on the key immune system cells that cause allergic reactions. Cross-linking these receptor molecules short-circuited the type of allergic reaction that leads to asthma, allergic rhinitis, and even the potentially deadly anaphylaxis caused by food allergy.

"This work represents an entirely new approach to treating allergic diseases," says NIAID Director Anthony S. Fauci, M.D. "The prevalence of allergic disease has increased significantly in recent decades, and there simply are not many promising therapeutic strategies out there. We hope that NIAID's continued support of research into the mechanisms of allergy will lead to other innovative concepts like this one."

"This research does what science is supposed to do," says Marshall Plaut, M.D., chief of NIAID's Allergic Mechanisms Section. "The researchers succeeded in translating a scientific observation into a clever therapeutic idea." Details of this work, performed by a team of scientists at the University of California at Los Angeles (UCLA) and the University of New Mexico, appear in the May issue of Nature Medicine.

The scientists designed and created a molecule called GE2 that acts on two types of immune system cells central to allergic reactions: mast cells and basophils. In people with allergies, these cells respond to ordinarily harmless substances, such as pollen or peanut proteins, by releasing chemicals such as histamine that trigger the symptoms of allergic reactions. Histamine, for example, causes swelling, sneezing, itching, and irritation.

GE2 binds to receptor molecules on mast cells and basophils that control the release of histamine. "One of these receptor molecules is like a gas pedal: it makes the allergic reaction go. The other receptor molecule is like a brake," explains senior author Andrew Saxon, M.D., director of the UCLA Asthma, Allergy, and Immunologic Disease Center. "However, in this case, the brake only works when coupled with the gas pedal. Therefore, we constructed GE2 so that one end 'steps on' the brake while the other end binds to the gas pedal. This cross-linking slows or stops the allergic reaction."

In laboratory tests on human mast cells and basophils, the higher the dose of GE2, the less histamine the cells released when stimulated by an allergen. In tests on mice, GE2 significantly reduced allergic skin reactions.

Although many more lab and animal studies will be necessary before this approach can be tested in humans, it has the potential to treat such diseases as allergic asthma, allergic rhinitis, chronic urticaria (hives), angioedema (hive-like swelling) and even the sometimes deadly anaphylaxis brought on by allergic reactions to certain foods such as peanuts, Dr. Saxon says.

The GE2 molecule is called a fusion protein because its two active parts are connected, or fused, by a linking section. As it is constructed now, GE2 contains generic active parts that indiscriminately block reactions to any allergen, Dr. Saxon says. However, a fusion protein like GE2 could be designed to contain a specific allergen such as a peanut protein and thereby block only allergic reactions to peanut. These allergen-specific fusion proteins could be used in allergy shots to make them safer and more effective: The patient could receive higher doses of allergen in the shot, making it more effective, without running the risk of suffering a dangerous allergic reaction, because the "braking end" of the fusion protein would stop that reaction.

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, illness from potential agents of bioterrorism, tuberculosis, malaria, autoimmune disorders, asthma and allergies.

Press releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov. Reference: D Zhu et al. A novel human Fcy-Fce bifunctional fusion protein inhibits FceRI-mediated degranulation. Nature Medicine 8(5):518-21 (2002).