Researchers provide more insight into treatment of severe asthma
Kawakami and his colleagues are working to understand how these HRF and antibody interactions drive dangerous allergic reactions.
LA JOLLA: Many individuals are unaware of how serious asthma may be. Asthma is thought to be the cause of ten American deaths each day, 439,000 hospital admissions per year, and 1.3 million visits to emergency rooms.
“Asthma is one of the most important allergic diseases to study,” said Professor Toshiaki Kawakami, M.D., Ph.D., a member of the Center for Autoimmunity and Inflammation at La Jolla Institute for Immunology (LJI).
Kawakami and his LJI colleagues recently looked into the molecular causes of severe asthma and exacerbations of rhinovirus-induced asthma, a type of asthma that can occur along with a cold. Their research, which was just published in The Journal of Allergy and Clinical Immunology, suggests that individuals with both types of asthma may gain advantages from treatments that prevent interactions between a molecule known as histamine-releasing factor (HRF) and antibodies known as immunoglobulin E (IgE).
As Kawakami explains, many people with severe asthma aren’t responsive to current asthma therapies. He hopes two potential drug strategies from his laboratory might inhibit HRF and IgE interactions and deliver relief for these patients. “We hope this approach can be a means of treating severe asthma and asthma exacerbation,” he says.
Immune cells work as a team, and they secrete molecules to “talk” to each other. One of these molecular messengers is HRF, which is made by many types of cells, including lung epithelial cells and immune cells called macrophages. When a person encounters an allergen, these cells start churning out more HRF. The HRF then courses through the body and looks for special antibodies to bind to. HRF has several different kinds of antibody partners, however, and each interaction sends a different message to the surrounding immune cells.
Kawakami and his colleagues are working to understand how these HRF and antibody interactions drive dangerous allergic reactions. Over the last decade, the researchers have shown that HRF interactions with the IgE antibody drive harmful inflammation in mouse models of asthma.
Their new study is important because it sheds light on how this same HRF and IgE interaction triggers inflammation and drives asthma in humans. For the study, Kawakami collaborated with clinicians and scientists at the University of Pittsburgh School of Medicine; Children’s Hospital, Boston; and the University of Virginia to investigate the role of HRF across many patient groups.
Working with this large range of patient samples was critical. “Asthma isn’t just one disease,” Kawakami says. There are different forms of asthma, called “endotypes,” and current asthma therapies don’t work for all patients. Truly understanding and treating asthma means gathering data from every patient group possible.
The team found that HRF and IgE interactions drive inflammation specifically in patients with severe asthma and patients with rhinovirus-induced asthma exacerbation. These findings in humans are in line with the lab’s previous findings in mice.
The scientists further confirmed the importance of HRF and IgE interactions in laboratory experiments using a line of human bronchial cells. Kawakami and his colleagues observed a dramatic increase in HRF secretion when they infected these cells with rhinovirus. They saw the same dramatic increase when they exposed the bronchial cells to proteins from house dust mites (a very common allergen and asthma trigger).
Kawakami now hopes to test two potential asthma therapies. The first therapeutic approach would harness a molecule developed by the Kawakami Lab. This molecule, termed HRF-2CA, appears to inhibit asthma and severe food allergy symptoms in mice, and there’s reason to think they could help treat humans as well.