The histamine releasing factor (HRF) molecule has been identified by researchers at La Jolla Institute for Allergy & Immunology, as a potential target for developing novel therapies for numerous allergic reactions, including asthma. The study is published online in the Journal of Clinical Investigation.

In addition, the team, led by Toshiaki Kawakami, M.D., Ph.D., is the first to illuminate the HRF molecule in promoting asthma and some allergies, including identifying its receptor – a significant discovery that answers a vital 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), stated that the discoveries give novel insights on the function of HRF in allergic diseases.

Rivera explains:

“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. 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 disease.”

The investigation highlights the development of novel treatments based on obstructing HRF interactions with specific antibody (IgE) molecules, which have long been known to be the principal causes of allergies. Furthermore, the scientists identified two peptides (N19 and H3) as powerful treatment candidates for obstructing the HRF and IgE interactions. Peptides are protein fragments which stimulate various molecular actions. N19 and H3 prevent the interactions of the HRF and IgE molecules, thus stopping the allergic cascade in mouse models.

Dr. Kawakami, lead scientist, explained:

“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.”

Hannah Gould, Ph.D., a professor and prominent allergy researcher at King’s College in London, explained that the findings improved scientific understanding in numerous vital ways.

Gould said:

“The research community has long believed that the histamine releasing factor (HRF) played some role in triggering allergic responses and asthma in certain individuals. 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. We can look forward to future results of pre-clinical and clinical studies in the human system.”

Over the last few decades, the prevalence of asthma has been significantly increasing, reaching epidemic levels in the United States and other developed countries. In the U.S., 20 million individuals have asthma, including 9 million children. In developed countries, 10% to 20% of the population suffer from some type of allergies – both immune system disorders and illnesses.

Mitchell Kronenberg, Ph.D., president and chief scientific officer of the La Jolla Institute, a world leader in immune system research, explained:

“There is a huge need to understand these diseases and to find therapeutic interventions. 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 1960’s. Dr. Kawakami’s latest discovery is in keeping with our history of innovation in allergy research.”

Allergic reaction occurs when the immune system starts fighting substances in the environment (allergens) that are usually harmless, such as pollen, dust, dust mites, or a medicine. When the immune system is exposed to an allergen, IgE molecules stimulate white blood cells called mast cells and basophils. These cells release histamine as well as other compounds, which produce allergy symptoms that can vary from irritating to dangerous. In asthma, allergens which are inhaled can trigger wheezing shortness of breath, coughing and airway inflammation.

According to Dr. Kawakami, the HRF molecule has been researched for numerous years and was believed to be a contributory factor in the cellular interactions leading to asthma and allergies, but the specific purpose of the HRF molecule and mode of operation was previously unclear.

Dr. Kawakami, explained:

“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.”

Several factors have limited HRF research, such as not being able to model HRF interactions in mice. Furthermore, Dr. Kawakami explained that progress was also slowed as a result of failure to identify the HRF receptor.

Dr. Kawakami said:

“It’s very, very unusual for many years to pass between the discovery of a molecule and the identification of its receptor. In this case, 15 years had passed. Without the receptor, we couldn’t understand the role of this protein in asthma and allergies.”

In 2007, Dr. Kawakami and his team where the first to solve this case – identifying a subset of IgE and IgG molecules as HRF receptors. This discovery enabled Dr. Kawakami and his group to map the role of HRF in allergy activation.

In addition, the team found that substantial heterogeneity exists in the IgE molecules. Funded by NIH, the original study served as the foundation for the latest discoveries on HRF’s role in activating allergies. Dr. Kawakami said:

“The differences were big in terms of affecting the activation and survival of mast cells. 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.”

According to their findings, 20% to 30% of IgE molecules can interact with HRF molecules and generate mast cell activation leading to allergies.

Dr. Kawakami, said:

“We think HRF is important for amplifying allergic reactions initiated by IgE
and an allergen.”

The discoveries are published in the report entitled, Proinflammatory role of histamine-releasing factor in mouse models of asthma and allergy.

Written by Grace Rattue