Blood test results from hayfever victims testing an experimental anti-allergy drug have led investigators at the Johns Hopkins Asthma and Allergy Center to discovery of an essential immune system feedback loop that appears to be a basic mechanism driving all allergies. The biochemical loop, the scientists say, links the amount of immunoglobulin E (IgE) antibody, overabundant in people with allergies, to the number of immune cell IgE receptors, which, upon exposure to allergens, trigger a cascade of biological events that cause wheezing, sneezing, itching and swelling so common this time of year.
When volunteers took an experimental anti-IgE drug, the amount of circulating anti-IgE dropped by as much as 99 percent. But the Hopkins team, led by Donald MacGlashan Jr., M.D., Ph.D., suspected another factor contributed to the drug's anti-allergy effects.
They were right. In 1997 the team found the number of IgE receptors on certain immune cells plummeted alongside the drop in IgE, like two rocks rolling down the same hill. Together, the decreases stanched the allergic cascade, preventing symptoms in patients in clinical trials of the drug.
Continuing this work in the current study, the team discovered that when patients stopped taking the drug, not only did IgE bounce back to pretreatment levels, but immune cells sprouted new receptors, increasing from just a few thousand per cell to pretreatment levels of 200,000 or more over a few months.
The Hopkins team documented this feedback loop in lab tests and, for the first time, in patients, confirming what they had long suspected: that IgE antibodies and IgE receptors wax and wane together, linked somehow in a complex dance.
"To stop allergies, you need to maintain low counts of both IgE antibodies and IgE receptors," says Sarbjit Saini, M.D., lead author on the study, which appears in the May Journal of Immunology. "A slight increase in either restores the amount of histamine released." And, he said, this is probably true of all or most allergies.
That means a return of annoying symptoms, because histamine is the major chemical responsible for them. Histamine gets dumped into mucous membranes and the bloodstream by immune cells called basophils and mast cells. In people with allergies, excess circulating IgE docks with IgE receptors on the surface of these cells, priming them to react when they encounter allergens such as dust mites and pollen. When bits of pollen bump into primed mast cells and basophils, the cells release histamine and other agents that cause irritating symptoms.
Current over-the-counter remedies block symptoms while the underlying IgE-driven allergic process continues unabated. But anti-IgE disrupts the process by disabling IgE, sticking to the section IgE needs to bind to the cell surface receptors, says Bruce Bochner, M.D., a researcher on the study who is continuing his earlier work on anti-IgE.
"Anti-IgE has the potential to prevent allergies, no matter what you're allergic to. And it works as long as people stay on it," says Bochner.
Anti-IgE, in a version called rhuMAb-E25, is undergoing late-stage clinical trials in hundreds of patients worldwide at several hospitals, including Hopkins. Genentech Inc. (San Francisco), Novartis Pharma AG (Switzerland), and Tanox Biosystems Inc. (Houston), developed the drug and are funding the trials.
Saini, Bochner and colleagues took advantage of these clinical trials to glean data for their IgE study.
"The principal mission at academic medical centers is to learn as much as possible from patient trials. This one offered a wonderful opportunity to discover something important about the basic biology of allergies," says Bochner. The current study continues a long line of allergy and asthma research at Hopkins, where IgE and its role in allergies has been intensively investigated for decades. Researchers Teruka and Kimishige Ishizaka were among the first to isolate and describe IgE in the 1960s.
Funding for the study came from the National Institutes of Health, the Burroughs Wellcome Fund and Genentech Inc.
Co-authors include Sherry A. Sterbinsky, M.A.M.S, Alkis Togias, M.D., Daniel C. Adelman, M.D., and Lawrence M. Lichtenstein, M.D., Ph.D.
-- JHMI --
Relevant Web sites:Hopkins Division of Allergy and Clinical Immunology -- http://www.med.jhu.edu/allergy/
Health on the Net (HON) Foundation's IgE background -- http://www.hon.ch/Library/Theme/Allergy/Glossary/ige.html
Genentech press release on anti-IgE -- http://www.gene.com/pressrelease/1998/11_09_98.html
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