New molecular candidates for treatment of asthma and allergies

(December 1, 2011) La Jolla Institute for Allergy & Immunology scientists have identified the histamine releasing factor (HRF) molecule as a promising target for developing new treatments for a number of allergic reactions including asthma.

The research team, led by Toshiaki Kawakami, M.D., Ph.D., is also the first to clarify the role of the HRF molecule in promoting and some allergies, including identifying its receptor – a major finding that answers a long-held and important question in the allergy research community.

Juan Rivera, M.Sc., Ph.D., deputy scientific director at the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the National Institutes of Health (NIH), said the findings provide new insights on HRF's function in allergic diseases. "Importantly, this work advances both the understanding of how HRF contributes to susceptibility of certain individuals in developing allergic disease as well as begins to unravel the mechanisms involved," he said. "What is most encouraging is the demonstration that the effect of HRF to enhance allergic responses can be blocked, thus suggesting the possibility of new therapeutic strategies in allergic diseases."

The research study points to the development of new therapies based on blocking HRF interactions with certain antibody (IgE) molecules, long known to be central causes of allergies. The new study also found two novel peptides (N19 and H3) as strong therapeutic candidates for blocking the HRF and IgE interactions. Peptides are protein pieces which spur various molecular actions. The two peptides inhibit the interactions of the HRF and IgE molecules, thereby stopping the allergic cascade in mouse models.

"Based on our preliminary studies, we believe these HRF inhibitors may provide a new, innovative therapeutic avenue for the treatment of asthma and some allergies," said Dr. Kawakami, lead scientist on the study, published online today in the Journal of Clinical Investigation.

Hannah Gould, Ph.D., a professor and prominent allergy researcher at King's College in London, said the study advanced scientific understanding in several key ways. "The research community has long believed that the histamine releasing factor (HRF) played some role in triggering allergic responses and asthma in certain individuals," she said. "However, the identity of the primary binding partner, the HRF receptor, the unique characteristics of the IgE in these individuals, and the mechanisms involved in HRF activity have remained elusive until the present study by Dr. Kawakami and his team."

"These findings suggest a potential treatment for allergy and asthma patients who have HRF reactive IgE," she continued. "We can look forward to the future results of pre-clinical and clinical studies in the human system."

The prevalence of asthma has been dramatically increasing for the last few decades and has reached epidemic proportions in the U.S. and other industrialized countries. Twenty million patients suffer from asthma in the U.S. alone, including nine million children. Meanwhile, 10 to 20 percent of the population of industrialized countries suffers from some form of allergies. Both illnesses are immune system disorders.

"There is a huge need to understand these diseases and to find therapeutic interventions," said Mitchell Kronenberg, Ph.D., president and chief scientific officer of the La Jolla Institute, a world leader in immune system research. "Allergies and asthma are a cornerstone of the La Jolla Institute's research activities dating back to our founding scientists, who were the discoverers of the IgE molecule in the 1960s. Dr. Kawakami's latest discovery is in keeping with our history of innovation in allergy research."

Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment, referred to as allergens. When exposed to an allergen, IgE molecules activate white blood cells called mast cells and basophils. These cells release histamine and other compounds, which produces allergy symptoms that can range from uncomfortable to dangerous. In asthma, inhaled allergens can induce airway inflammation, causing wheezing, coughing and shortness of breath.

Dr. Kawakami said the HRF molecule has been studied for many years and was thought to play some role in the cellular interactions leading to allergies and asthmas. However, its exact purpose and mode of operation was previously not clear. "Nasal drainage, skin blister fluids, and some bronchial fluids were found to contain HRF secretions, so the scientific community suspected that HRF was important, but we didn't know why," said Dr. Kawakami.

HRF studies had been limited by several factors over the years, he added, including the inability to model HRF interactions in mice. In addition, Dr. Kawakami said failure to identify the HRF receptor also slowed progress. "It's very, very unusual for many years to pass between the discovery of a molecule and the identification of its receptor," he said. "In this case, 15 years had passed. Without the receptor, we couldn't understand the role of this protein in asthma and allergies."

Dr. Kawakami and his team were the first to solve this mystery in 2007 -- identifying a subset of IgE and IgG molecules as HRF receptors. This information gave Dr. Kawakami's group the critical missing piece of the HRF puzzle and enabled the researchers to map HRF's role in allergy activation.

Dr. Kawakami's team also previously discovered that tremendous heterogeneity exists in the IgE molecules. The original work, funded by NIH, provided the foundation for the latest findings on HRF's role in triggering allergies. "The differences were big in terms of affecting the activation and survival of mast cells," he said. "That's why we got interested in this molecule (HRF). Earlier studies had suggested that HRF does not bind to IgE molecules. But I was not convinced, so I decided to explore this further."

Their study results showed that 20 to 30 percent of IgE molecules can interact with HRF molecules and produce mast cell activation leading to allergies. "We think HRF is important for amplifying allergic reactions initiated by IgE and an allergen," said Dr Kawakami. The findings were published today in a paper entitled, Proinflammatory role of histamine-releasing factor in mouse models of asthma and .

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