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NIAID Researchers Go Nose-to-Nose Against Allergies
By Jennifer Wenger
While NIAID is often linked with current headline-grabbers such as biodefense, AIDS and SARS, it's the "A" part of the institute's name that may mean the most to the more than 50 million Americans who suffer from hay fever, sinusitis, asthma, anaphylaxis and other allergy-related illnesses.
"Allergies are the sixth leading cause of chronic disease in the United States and the number of cases continues to rise," said Dr. Dean Metcalfe, chief of the Laboratory of Allergic Diseases (LAD). "Their prevalence within the population has made this an all-important area of exploration for NIAID intramural scientists for the past 50 years."
LAD, created in 1995, is one of NIAID's clinical research labs, encompassing facilities in Rockville and the Clinical Center, and housing approximately 45 employees. Researchers there strive to understand how and why the body wages war against perceived intruders not bacteria, viruses or other germs, but the seemingly benign materials found in carpets and couch cushions, in foods, or wafting through open windows. Materials that can provoke an allergic reaction commonly referred to as allergens include pollen, animal dander, dust mite and cockroach droppings, insect stings, mold spores, latex, certain drugs, and some foods such as milk, peanuts and shellfish.
Key to any allergic reaction is an antibody known as immunoglobulin E, or IgE. Usually considered "good guys" in the body's defense system, antibodies are proteins that are custom-built by the body to bind to and help destroy foreign substances such as viruses and bacteria. However, when someone with allergies is exposed to an allergen such as pollen, he or she produces bulk quantities of IgE antibodies that recognize and bind to the pollen. Mast cells granule-containing white blood cells that reside in mucous membranes and other tissues beneath the skin have receptors that seek out IgE antibodies and attach them to their surfaces.
When that same person encounters pollen a second time, clusters of IgE molecules, now protruding from the mast cell's surface, bind to the pollen grain, signaling the mast cell to release its toxic contents into the surrounding tissues. One such toxin known as histamine makes blood vessels "leaky," allowing fluids to seep out of nearby capillaries and, on cue, causing the eyes to water and the nose to run. Histamine also causes smooth muscle, such as the muscle surrounding a person's bronchial tubes, to contract, leading to shortness of breath. Asthma, a condition in which the airways become inflamed and constricted, is believed to be an allergic reaction to substances breathed through the air.
Once mast cells have emptied their contents, additional players are summoned to the scene. Basophils, like mast cells, are granule-containing white blood cells that link up with IgE antibodies and empty their toxic contents when IgE molecules bind with the allergen. Eosinophils, one of the late arrivals at the site of inflammation, can turn an acute reaction into a chronic one by sustaining the attack as long as the allergen persists in the environment.
What Animal Models Teach
Not surprisingly, IgE antibodies, mast cells, basophils and eosinophils, in addition to a host of other players, are of keen interest to allergy researchers. Once scientists better understand the root cause of allergies and how they can lead to more serious health problems, better ways can be developed to diagnose and treat people who suffer from them.
Researchers in the allergic inflammation section are working to understand how a person can develop tolerance to certain allergens naturally. They want to learn how roughly 75 percent of the U.S. population manages to escape an allergic reaction unscathed even though they are exposed to the same environmental substances as the 25 percent who do have allergies. Section head Dr. Andrea Keane-Myers and colleagues are conducting experiments to learn more about an intriguing phenomenon in which people who have parasitic infections, such as those contracted in developing countries, are able to develop immunity to allergic reactions.
"If we can understand the mechanisms by which individuals develop a tolerance to allergens, we can perhaps use these same mechanisms to develop therapeutics for people with allergies," said Keane-Myers.
People with parasitic infections, like people who suffer from allergies, produce large quantities of IgE antibodies, which, in turn, link up to mast cells, eosinophils and basophils. (When mast cells, basophils and eosinophils respond to parasite invasion, the granules released will kill the parasite.) Scientists believe that parasitic infections help ward off allergic reactions to ensure that the parasite's host continues to offer a hospitable environment in which to live. Whether or not allergic symptoms appear, however, is influenced by the severity of the parasitic infection, Keane-Myers has found.
Just as a driver depends on his car's sensors to tell when the engine is too hot or the oil level too low, every cell in the body has receptors on its surface to help it detect what's going on in its environment. How receptors enable a cell to respond to these environmental cues is the focus of two sections of the laboratory.
In the molecular signal transduction section, researchers are zeroing in on chemical signals that direct cellular activities during an asthma attack. Dr. Kirk Druey, head of the section, has identified a protein that may help thwart the sequence of events by which an allergic reaction develops into asthma, a finding that could one day lead to the development of more effective anti-inflammatory drugs.
Natural killer (NK) cells, though not directly related to allergies, are giving researchers added insight into the mechanisms by which cells respond to their environment. One of the first lines of defense against virus-infected cells, bacteria or tumor cells, NK cells have receptors that, if unchecked, could signal the destruction of every cell in their path. But a second kind of receptor on the NK cell one that interacts with molecules found only on normal, healthy cells can turn off the killing action of the NK cell, overriding the activating receptor and shielding the normal cell from injury. Dr. John Coligan, head of the receptor cell biology section, and his research team have identified an inhibitory receptor in rats that is continuously recycled to the NK cell's surface. In this way, normal cells are offered a ready supply of inhibitory receptors with which to bind.
Exploring Rare Mast Cell Disorder
Currently, about 10 clinical protocols are being conducted at the CC on various topics related to allergy, immunology and mast cell disorders.
Of compelling interest to clinical researchers in the laboratory's mast cell biology section is a disease known as mastocytosis, a relatively uncommon disorder affecting thousands of Americans. Mastocytosis is caused by an overabundance of mast cells in the skin, bone marrow, gastrointestinal tract, or internal organs such as the liver and spleen. Individuals with the disorder usually have brownish skin lesions, one of the disease's major diagnostic characteristics. Other symptoms can include bone or muscle pain, abdominal discomfort, stomach ulcers, diarrhea, faintness and shock.
"Some people ask why we would dedicate ourselves and laboratory resources to the study of mastocytosis when it affects such a relatively small number of people," said Metcalfe, who also heads the section. "But by studying a disease that is marked by a proliferation of mast cells, we are examining the biology of mast cells themselves, namely how they grow, develop and so on. Such information will provide greater insights into allergies and other related illnesses that affect a much larger segment of the population."
One of the more significant developments from the laboratory's work on mastocytosis occurred this past year when personnel of the section successfully developed several human mast cell lines that can be grown in culture. (Because mast cells live in tissues, not blood, no one to this point had been able to harvest them for study.) Grown from stem cells, these mast cells possess receptors that can be activated by allergens, making them a very promising resource for researchers worldwide.
In the clinical allergy and immunology unit, headed by Dr. Calman Prussin, scientists are exploring how a person's immune system recognizes and responds to certain allergens. Before T cells react to an allergen, they rely on a "go-between" player called an antigen-presenting cell to present the allergen to them in a recognizable way, much like a diplomat requires an interpreter to convey information in a home language. Researchers in the unit are studying how special antigen-presenting cells known as dendritic cells present information to T cells to produce allergic inflammation.
The group is also studying the effects of omalizumab (Xolair), a drug approved by the FDA in June 2003 that reduces the level of IgE antibodies in the blood. Prussin and others are now trying to determine whether the reduction in IgE receptors could ultimately result in the activation of fewer T cells, preventing allergic inflammation.
One of the unit's more noteworthy accomplishments to date is development of staining techniques that differentiate between Th2 cells, T cells that are heavily involved in the allergic response, and Th1 cells, which are not involved.
"These techniques allow us to examine allergen-specific T-cell function with unprecedented detail," said Prussin. As new allergy drugs become more fine-tuned, he says, researchers will be able to directly monitor how to use such drugs to change T-cell responses. And with increased scrutiny comes better control over an allergic response.
"We'll be able to look at different ways to tweak the allergic immune response and develop the means to drive it in the desired direction," he noted.
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