Investigators at the Johns Hopkins Asthma and Allergy Center (Baltimore) have discovered an essential immune system feedback loop that appears to be a basic mechanism driving all allergies. Blood test results from hayfever victims testing an experimental anti-allergy drug led the researchers to the discovery.
Tthe Hopkins team, led by Donald MacGlashan Jr., say that the biochemical loop links the amount of immunoglobulin E (IgE) antibody, overabundant in people with allergies, to the number of immune cell IgE receptors. Upon exposure to allergens, IgE receptors trigger a cascade of biological events that cause wheezing, sneezing, itching, and swelling.
When volunteers took an experimental anti-IgE drug, the amount of circulating anti-IgE dropped by as much as 99%. But the researchers suspected another factor contributed to the drug's anti-allergy effects.
They were proven right in 1997, when they found that the number of IgE receptors on certain immune cells plummeted alongside the drop in IgE. 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.
To stop allergies, you need to maintain low counts of both IgE antibodies and IgE receptors, says Sarbjit Saini, 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 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, 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."
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 (Basle, 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.
Funding for the study came from the National Institutes of Health, the Burroughs Wellcome Fund, and Genentech Inc. Co-authors include Sherry A. Sterbinsky, Alkis Togias, Daniel C. Adelman, and Lawrence M. Lichtenstein
For more information: Donald MacGlashan, Professor of Clinical Immunology, Johns Hopkins University School of Medicine, 720 Rutland Ave., Baltimore MD 21205. Tel: 410-550-2145. Email: email@example.com.