Stanford Report, July 21, 2004

Protein discovery may provide clue to controlling allergic reactions

Mice lacking protein developed condition similar to eczema

BY MITZI BAKER

Scientists know a lot about how an allergic reaction works. What they don’t know is how to stop the body’s immune system from launching an attack when it detects the presence of pollen or dust. But a recent discovery by Stanford researchers in mice could be a step toward quelling an overly zealous immune system.

Those who study the allergic reaction, like Stephen Galli, MD, the Mary Hewitt Loveless, MD, Professor and chair of pathology, have long known that immune cells called mast cells defend against parasitic invasions. When triggered, these cells release noxious chemicals such as histamine, which help incapacitate the invaders. However, those chemicals also cause the wheezing of asthma, the itching of eczema, the sneezing of hay fever and, in extreme cases, the life-threatening shock of anaphylaxis.

For years, Galli and his colleagues have been teasing apart the complicated molecular chain reactions involved in allergies. In the August issue of Nature Immunology, they report the discovery of a new protein – called RabGEF1 – that stifles the allergic reaction of mast cells in mice.

In an effort led by senior research scientist Mindy Tsai, DMSc., the team bred mice that lacked RabGEF1 to see if the lack of the protein had any effect. The deficient mice developed a severe skin condition that is similar to eczema in humans. These mice also had more mast cells than a normal mouse and those cells released more of the chemicals associated with allergic responses.

The effect of the absence of this protein in mice indicates that it plays a critical role in keeping the allergic reaction in check, said See-Ying Tam, PhD, senior research scientist in pathology and first author of the paper.

Though excited about this first demonstration of the protein’s role, the team is cautiously optimistic about its future as a therapy for mast-cell dependent disorders in humans.

“What this reveals is a completely new and important negative regulator, or brake, on a reaction that lies at the heart of diseases with tremendous morbidity and mortality, like asthma,” Galli said. “We think this is a very interesting potential target, but a lot of work would have to be done to demonstrate that it is clinically useful.”

Other Stanford researchers who contributed to this work are: Janet Kalesnikoff, Didier Scherrer (now at Entelos Inc.), Susumu Nakae, Devavani Chatterjea and Donna Bouley.