Blocking Immune System ‘Messenger’ May Treat Severe Asthma

Asthma is more dangerous than many people realize. An estimated 10 Americans die every day from asthma, and the disease leads to around 439,000 hospitalizations and 1.3 million emergency room trips each year.

In a new study, Kawakami and his colleagues at LJI investigated the molecular drivers of severe asthma and rhinovirus-induced asthma exacerbation (a type of asthma that can accompany a common cold). Their findings, published recently in The Journal of Allergy and Clinical Immunology, suggest people with both types of asthma may benefit from therapies that block interactions between a molecule called histamine-releasing factor (HRF) and antibodies called immunoglobulin E (IgE).

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.

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.

“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.

The researchers are also interested in studying a therapeutic antibody called SPF7-1, which acts as a sort of HRF decoy, binding to IgE and blocking interactions with the real HRF.

“The best way forward would be to carry out clinical trials to study these two therapeutic options,” says Kawakami.


Yu Kawakami, Ikuo Takazawa, Merritt L. Fajt, Kazumi Kasakura, Joseph Lin, Julienne Ferrer, David B. Kantor, Wanda Phipatanakul, Peter W. Heymann, Chris A. Benedict, Yuko Kawakami, Toshiaki Kawakami. Histamine-releasing factor in severe asthma and rhinovirus-associated asthma exacerbation. Journal of Allergy and Clinical Immunology, 2023; DOI: 10.1016/j.jaci.2023.04.021

La Jolla Institute for Immunology. (2023, June 12). Blocking immune system ‘messenger’ may treat severe asthma: Finally beating asthma might hinge on blocking HRF and IgE interactions. ScienceDaily. Retrieved June 19, 2023 from

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