Blocking the motion of calcium signals in immune cells suppresses essentially the most common type of asthma, but without compromising the body’s defenses against flu viruses, a latest study finds.

Led by researchers at NYU Grossman School of Medicine, experiments showed that removing the gene for a calcium channel – specifically the calcium release-activated calcium (CRAC) channel made up of ORAI1 proteins – thoroughly reduced asthmatic inflammation within the lungs of mice attributable to house dust mite feces, a typical reason behind allergic asthma. Blocking signals sent through this channel with an investigational latest drug called a CRAC channel inhibitor had an identical effect.

The study revolved around the usage of charged particles, mainly calcium, by human cells to send signals and flip biological switches. When triggered–­–whether by viral proteins or allergens -; immune cells called T cells open channels of their outer membranes, letting calcium rush in to activate signaling pathways that control cell division and secretion of cytokine molecules that help T cells communicate with other immune cells.

Past work had found that CRAC channels in T cells regulate their ability to multiply into armies of cells designed to fight infections attributable to viruses and other pathogens.

Published online in Science Advances on October 7, the brand new study showed that the CRAC channel inhibitor reduced allergic asthma and mucus build-up in mice without sabotaging their immune system’s ability to fight influenza, a important worry of researchers looking for to tailor immune-suppressing drugs for several applications.

Our study provides evidence that a latest class of medicine that focus on CRAC channels may be used safely to counter allergic asthma without creating vulnerability to infections. Systemic application of a CRAC channel blocker specifically suppressed airway inflammation in response to allergen exposure.”

Stefan Feske, MD, Senior Study Creator, the Jeffrey Bergstein Professor of Medicine, Department of Pathology, NYU Langone Health

About 25 million Americans suffer from asthma, with repeated episodes of wheezing, breathlessness, chest tightness, and coughing, in response to the Centers for Disease Control and Prevention. Nearly all of those have asthma related to inhaled allergens, say the study authors.

Targeting calcium channels

Allergic asthma is characterised by increased type 2 (T2) inflammation, which involves a subset of T cells called T helper (Th) 2 cells, say the study authors. Th2 cells produce cytokines that play necessary roles in each normal immune defenses, and in disease-causing inflammation that happens within the flawed place and amount. In allergic asthma, cytokines promote the production of an antibody type called IgE and the recruitment to the lungs of inflammation-causing immune cells called eosinophils, the hallmarks of the disease.

In the brand new study, the research team found that genetic deletion of ORAI1 in T cells, or treatment of mice with the CRAC channel inhibitor CM4620, thoroughly suppressed Th2-driven airway inflammation in response to deal with dust mite allergens. CM4620 is under development by the corporate CalciMedica, which partnered with NYU Langone in the present study, and is in phase 2 clinical trials for COVID-19 associated pulmonary inflammation and acute pancreatitis.

Treatment with CM4620 significantly reduced airway inflammation compared to an inactive control substance, with the treated mice also showing much lower levels of Th2 cytokines and related gene expression. Without calcium entering through CRAC channels, T cells are unable to turn into Th2 cells and produce the cytokines that cause allergic asthma, the authors say.

Conversely, ORAI1 gene deletion, or interfering with CRAC channel function in T cells via the study drug, didn’t hinder T cell-driven antiviral immunity, as lung inflammation and immune responses were similar in mice with and without ORAI1.

“Our work demonstrates that Th2 cell-mediated airway inflammation is more depending on CRAC channels than T cell-mediated antiviral immunity within the lung,” says study co-first writer Yin-Hu Wang, PhD, a post-doctoral fellow within the Feske lab. “This implies CRAC channel inhibition as a promising, potential future treatment approach for allergic airway disease.”

Source:

NYU Langone Health / NYU Grossman School of Medicine

Journal reference:

Wang, Y-H., et al. (2022) Distinct roles of ORAI1 in T cell-mediated allergic airway inflammation and immunity to influenza A virus infection. Science Advances. doi.org/10.1126/sciadv.abn6552.