Blocking the action of calcium signals in immune cells suppresses the most common form of asthma, but without compromising the body’s defenses once morest asthma, a new study finds. virus flu.
Led by researchers from the Grossman School of Medicine at the University of New Yorkexperiments have shown that the elimination of embarrassed of a calcium channel – specifically the calcium release-activated calcium channel (CRAC) made up of ORAI1 proteins – significantly reduced asthmatic inflammation in the lungs of mice caused by dust mite feces, a common cause of asthma allergic. Blocking signals sent through this channel with a new medication experimental drug called 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 membrane, 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 revealed 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 Science Advances on October 7, the new study showed that the CRAC channel blocker reduced allergic asthma and the accumulation of mucus in mice without sabotaging their immune system’s ability to fight off the flu, a major concern for researchers seeking to adapt immunosuppressive drugs for multiple applications.
Our study proves that a new class of drugs targeting CRAC channels can be used safely to fight 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, lead study 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. According to the study authors, the majority of these people suffer from asthma linked to inhaled allergens.
Target calcium channels
According to the study authors, 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. Th2 cells produce cytokines that play an important role both in normal immune defenses and in pathological inflammation that occurs in the wrong place and in the wrong amount. In allergic asthma, cytokines promote the production of a type ofantibody called IgE and the recruitment to the lungs of immune cells responsible for inflammation, called eosinophils, which are 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 the CRAC channel blocker CM4620, completely suppresses Th2-induced airway inflammation. in response to dust mite allergens. CM4620 is being developed by CalciMedica, which has 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.
CM4620 treatment significantly reduced airway inflammation compared to an inactive control, with treated mice also showing significantly lower levels of Th2 cytokines and related gene expression. According to the authors, without the entry of calcium through CRAC channels, T cells are unable to transform into Th2 cells and produce the cytokines that cause allergic asthma.
Conversely, deletion of the ORAI1 gene, or interference with CRAC channel function in T cells via the study drug, did not impair T cell-mediated antiviral immunity, lung inflammation, and immune responses being similar in mice with and without ORAI1.
“Our work demonstrates that Th2 cell-mediated airway inflammation is more dependent on CRAC channels than T cell-mediated antiviral immunity in the lung,” says study co-first author Yin- Hu Wang, PhD, a Feske lab postdoc. “This suggests that inhibition of CRAC channels is a promising future therapeutic approach for allergic airway diseases. »
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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.