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May 18, 2000

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Researchers Present New Theory for Allergic Diseases

Johns Hopkins researchers have discovered, to their surprise, that a nervous system protein may have a significant role in asthma, hay fever and other allergies. According to the new research reported in the May issue of the American Journal of Respiratory and Critical Care Medicine, the protein, nerve growth factor (NGF), may be responsible for making allergy sufferers more sensitive to irritants such as tobacco smoke.

"Hay fever and asthma now seem to derive from events not only in the respiratory system, but also from a nervous system that is overreacting to stimuli," says Vassilis Koliatsos, M.D., an associate professor of pathology, neurology and neuroscience at the Johns Hopkins School of Medicine. In the United States, hay fever, medically known as allergic rhinitis, affects up to 36 million people and asthma affects about 14 million, at a cost of several billions of dollars per year. For decades, scientists have known that individuals who have allergies and asthma are more reactive to irritants such as cold, dry air and tobacco smoke, but until now, they haven't known why.

Hopkins allergy researchers took to the trail of NGF for several reasons. First, Koliatsos, who is an expert on the use of NGF in experiments to treat nerve and brain disorders, informed the allergy researchers that using NGF to treat Alzheimer's caused patients excessive pain. NGF, found naturally in the body, is a small, potent molecule that helps maintain certain nerve cells and prods other nerve cells to grow and communicate with others. "It looked like the pain syndromes we saw in these patients shared many of the same mechanisms with respiratory allergy," says Koliatsos. Specifically, both involved an inflammatory response by cells in lung or nerves. Secondly, Hopkins allergy researchers had found that individuals who were hyper-responsive to irritants had nerves in their airways that were abnormally reactive. And thirdly, researchers at Hopkins and other institutions had shown that, in animal studies, NGF could cause significant changes in nerve fibers. For example, mice that were genetically engineered to produce excessive amounts of NGF in their lungs developed increased density of nerves in the airways as well as increased responsiveness to irritants.

To test whether an allergic reaction in humans would increase NGF, Alvin Sanico, M.D., an assistant professor of medicine at Hopkins, and his colleagues enlisted 20 volunteers who had hay fever and 10 who were healthy. As part of the study, the scientists collected nasal washings before and after administering ragweed or grass pollen extracts by nasal spray. They found that baseline levels of NGF in the nasal washings of the allergic group were significantly higher compared to the healthy group. In addition, they discovered that exposure to the allergen caused a significant increase in NGF levels in the allergic group but had no effect on the healthy individuals.

"This finding provides further understanding of a very common disease and hopefully may open new possibilities for novel forms of treatment in the future," says Sanico, lead author of the study. For example, researchers in the future may identify a drug that could block the effects of these molecules and decrease hyper-responsiveness.

"Our frustrations with the side effects of NGF in clinical trials for Alzheimer's disease and nerve disorders helped lead to this study," says Koliatsos. "It is very rewarding to see another clinical opportunity for this very interesting molecule."

Sanico says the new discovery can bridge the two major features of allergic airway disease: inflammation (which causes typical allergy symptoms such as congestion) and hyper-responsiveness to irritants. During inflammation, cells that participate in an allergic reaction, such as mast cells and eosinophils, are stimulated, and these cells have now been shown to be capable of producing NGF. Sanico says more studies that are needed to further understand this new facet of allergic airway disease in humans are currently under way.

The study was funded by grants from the National Institutes of Health and Johns Hopkins. The authors of the study are Alvin Sanico, Todd Gleeson, Susan Bora, David Proud, Vassilis Koliatsos and Alkis Togias from Johns Hopkins in Baltimore, Maryland, as well as John Bienenstock and Andrzej Stanisz from McMaster University in Ontario, Canada.


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