NEW YORK, Oct. 7, 2022 /PRNewswire/ -- 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, a new study finds.
The study revolved around the use 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 in their outer membranes, letting calcium rush in to turn on 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 caused by viruses and other pathogens.
Published online in Science Advances on October 7, the 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 main worry of researchers seeking to tailor immune-suppressing drugs for several applications.
"Our study provides evidence that a new class of drugs that target CRAC channels can be used safely to counter allergic asthma without creating vulnerability to infections," says senior study author Stefan Feske, MD, the Jeffrey Bergstein Professor of Medicine in the Department of Pathology at NYU Langone Health. "Systemic application of a CRAC channel blocker specifically suppressed airway inflammation in response to allergen exposure."
Allergic asthma is characterized 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 important roles in both normal immune defenses, and in disease-causing inflammation that occurs in the wrong 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.
Treatment with CM4620 significantly reduced airway inflammation when 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 become 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, did not 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 dependent on CRAC channels than T cell-mediated antiviral immunity in the lung," says study co-first author Yin-Hu Wang, PhD, a post-doctoral fellow in the Feske lab. "This suggests CRAC channel inhibition as a promising, potential future treatment approach for allergic airway disease."
Along with Feske and Wang, the study was led by co-first authors Lucile Noyer and Sascha Kahlfuss in the Department of Pathology at NYU Langone Health. Other NYU Langone researchers in this study were Dimitrius Raphael, Anthony Tao, Ulrike Kaufmann, Jingjie Zhu, Marisa Mitchell-Flack, Ikjot Sidhu, Fang Zhou, and Martin Vaeth. Also study authors were Sean Saunders and Paul Thomas of St. Jude's Children's Research Hospital in Memphis, and Maria Curotto de Lafaille at Mount Sinai School of Medicine in New York
. Kenneth Stauderman of CalciMedica Inc., La Jolla, California, was also a study author.
Feske is a cofounder of CalciMedica, which provided the CRAC channel inhibitor for the current study, while Stauderman is the chief science officer of CalciMedica. Both have financial interests in the company, with the relationships managed in accordance with the policies of NYU Langone.
The content of the article does not represent any opinions of Synapse and its affiliated companies. If there is any copyright infringement or error, please contact us, and we will deal with it within 24 hours.
Accelerate Strategic R&D decision making with Synapse, PatSnap’s AI-powered Connected Innovation Intelligence Platform Built for Life Sciences Professionals.
Start your data trial now!
Synapse data is also accessible to external entities via APIs or data packages. Empower better decisions with the latest in pharmaceutical intelligence.