Blocking the action of calcium signals in immune cells suppresses the most common form of asthma, but without compromising the body’s defenses against flu viruses, according to a new study.
Led by researchers at NYU Grossman School of Medicine, experiments showed that deleting the gene for a calcium channel – specifically the calcium release-activated calcium channel (CRAC) composed of ORAI1 proteins – significantly reduced the asthmatic inflammation in the lungs of mice caused by the house. dust mite droppings, a common cause of allergic asthma. Blocking the signals sent through this channel with an experimental new drug called a CRAC channel blocker had a similar effect.
The study focused on the use of charged particles, primarily calcium, by human cells to send signals and activate biological switches. When triggered – whether by viral proteins or allergens –; immune cells called T cells open channels in their outer membranes, letting calcium rush in to activate signaling pathways that control cell division and the secretion of cytokine molecules that help T cells communicate with other immune cells .
Previous work had shown that CRAC channels in T cells regulate their ability to multiply into armies of cells designed to fight infections caused by viruses and other pathogens.
Published online in Scientists progress On October 7, the new study showed that the CRAC channel blocker reduced allergic asthma and mucus buildup in mice without sabotaging their immune system’s ability to fight the flu, a major concern for researchers looking to adapt immunosuppressive drugs to several applications.
Our study provides evidence that a new class of drugs targeting CRAC channels can be used safely to counteract allergic asthma without creating vulnerability to infection.. Systemic application of a CRAC channel blocker specifically suppressed airway inflammation in response to allergen exposure.”
Stefan Feske, MD, Study Lead Author, Jeffrey Bergstein Professor of Medicine, Department of Pathology, NYU Langone Health
About 25 million Americans have asthma, with repeated episodes of wheezing, shortness of breath, chest tightness and coughing, according to the Centers for Disease Control and Prevention. The majority of them suffer from asthma linked to inhaled allergens, say the study authors.
Target calcium channels
Allergic asthma is characterized by an increase in type 2 (T2) inflammation, which involves a subset of T cells called T helper (Th) 2 cells, explain the study authors. Th2 cells produce cytokines that play an important role both in normal immune defenses and in pathogenic inflammation that occurs in the wrong place and in quantity. In allergic asthma, cytokines promote the production of a type of antibody called IgE and the recruitment to the lungs of inflammatory immune cells called eosinophils, hallmarks of the disease.
In the new study, the research team found that genetic deletion of ORAI1 in T cells, or treatment of mice with CRAC channel blocker CM4620, completely suppressed Th2-induced airway inflammation in response to dust mite allergens. CM4620 is being developed by CalciMedica, which partnered with NYU Langone in the current study, and is in Phase 2 clinical trials for lung inflammation and acute pancreatitis associated with COVID-19.
Treatment with CM4620 significantly reduced airway inflammation compared to an inactive control, with treated mice also showing significantly lower levels of Th2 cytokines and related gene expression. Without calcium entering through CRAC channels, T cells are unable to become Th2 cells and produce the cytokines that cause allergic asthma, the authors say.
Conversely, deletion of the ORAI1 gene or interference with CRAC channel function in T cells via study drug did not impair T cell-mediated antiviral immunity because inflammation pulmonary and immune responses were similar in mice with and without ORAI1.
“Our work demonstrates that Th2 cell-mediated airway inflammation is more dependent on CRAC channels than on T cell-mediated antiviral immunity in the lungs,” says study co-first author Yin- Hu Wang, PhD, postdoctoral fellow at the Feske laboratory. “This suggests that inhibition of CRAC channels is a promising and potential future therapeutic approach for allergic airway diseases.”
NYU Langone Health/NYU Grossman School of Medicine
Wang, YH., et al. (2022) Distinct roles of ORAI1 in T cell-mediated allergic airway inflammation and immunity to influenza A virus infection. Scientific advances. doi.org/10.1126/sciadv.abn6552.