Understanding Allergies By Mapping Chemical Structures Recognized By Immune System

LIAI, a nonprofit organization and one of the world's leading immunology research centers, will partner on the study with clinical researchers at the University of California, San Diego (UC San Diego) and the National Jewish Medical and Research Center in Denver, Colorado. Both centers will set up human subject protocols involving allergy sufferers who will donate blood for the LIAI study.

The study will involve 200 donors over five years and will look at 32 common allergen sources, such as trees, grasses, weeds, fungi, mites, insects and mammals. Food allergies are not part of the study.

Howard Grey, M.D., project co-investigator, said the study will push knowledge of allergies to a deeper level. "The whole field has been dominated by the analysis of the antibody response, because that's what causes many of the symptoms of the disease -- the sneezing, sniffling, coughing and so forth," he said, noting that the discovery of the immunoglobulin E (IgE) antibody in 1966 by Kimishige Ishizaka, M.D., Ph.D. and his wife, Teruko Ishizaka, Ph.D., who later helped launch LIAI, revolutionized allergy research.

"Now the scientific community has the tools to take our knowledge even further by analyzing T cell responses," he said. "It seems in keeping with our history that LIAI will now lead the next step -- breaking down the allergy response to its most basic molecular level."

Results from the project will be available to scientists worldwide via the NIAID's Immune Epitope Database (IEDB), the world's largest research database on how the immune system responds to infectious diseases, allergens and other agents. The database, developed by LIAI under an NIAID contract, is a public health tool designed to speed the development of vaccines and treatments by sharing important research data with scientists around the globe.

Mitchell Kronenberg, Ph.D., LIAI president & scientific director, said the project is a perfect fit with LIAI because it is developing the IEDB. In addition, allergies are a cornerstone of its immunology-focused research activities. "Many people may not be aware that the immune system plays a role in so many diseases -- from cancer to infectious diseases," he said. "Allergies are no exception, and result from inappropriate or overactive immune responses." Kronenberg said the study also enables further collaboration between LIAI, now located in the new Science Research Park at UC San Diego, and the University's researchers.

Sette said the project will map down to the level of molecules and atoms the chemical structures recognized by the immune system and which cause it to initiate an allergic reaction. "This has the potential to directly impact all people who are afflicted with allergies, because it may lead to new, more effective ways of diagnosing and treating these diseases." According to the NIAID, allergic diseases affect as many as 40 to 50 million Americans, and they are among the major causes of illness and disability in the United States. Allergies can also lead to asthma, a respiratory disorder that accounts for one-quarter of all emergency room visits in the U.S. each year.

LIAI researchers will identify the specific allergy epitopes that cause T cells to launch an attack against the allergens. Epitopes are tiny sites on a protein or other molecule that instigate a T cell response. "This opens the possibility of developing therapies around those epitopes," Grey said. "There have already been some clinical trials which are showing promise with the approach of treating patients with allergy-related epitopes. The information we're developing will provide the clinical community with the ability to try this approach with a wide variety of allergic diseases."

Currently, many allergy sufferers receive desensitization treatments, whereby the patient is given increasing doses of the substance causing allergy or allergen over a long period of time in order to develop immune tolerance to the allergen. The approach can be problematic because patients already have antibodies to the allergens, which can cause reactions, and because it is also a very lengthy process.

The idea behind the epitope-based therapies is that patients could be given small pieces or epitopes from the allergen that would be able to induce immune tolerance, without instigating an antibody reaction, Sette explained. If this proves true, it could produce the same effects as the current desensitization therapies, but in a much shorter period of time, and without the allergic side effects. "You would be desensitizing the cells (with the allergy epitopes), rather than activating them," he added.

Another important aspect of the research is analyzing the effects of regulatory T cells in the allergy process. This T cell type, which has only been discovered in the last decade, appears to suppress T cell reactions to allergens, rather than cause them. "We are hoping to find specific epitopes that activate these regulatory T cells," said John Sidney, project co-investigator. "If so, we might have an extremely powerful tool for treating allergy diseases."

LIAI's project efforts will be accelerated through bioinformatics along with the use of the allergy epitope information already in the IEDB. Bioinformatics uses computer databases, algorithms and statistical techniques to analyze biological information. "We developed the IEDB and we're going to take advantage of that huge resource to improve our epitope identification algorithms based on that data," said Bjoern Peters, Ph.D., project co-investigator. "We'll use those algorithms to statistically determine which allergy epitopes are most likely to trigger a T cell response and then test those assumptions in the lab. By using bioinformatics, we will greatly speed the development of the project data."