CRAC gene removal approach counters allergic asthma

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 in the lungs of mice caused by house dust mite feces, a common cause of allergic asthma.

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.

In the 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 house dust mite allergens.

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.

Reference:

Stefan Feske et al, Distinct roles of ORAI1 in T cell-mediated allergic airway inflammation and immunity to influenza A virus infection, Science Advances, DOI: 10.1126/sciadv.abn6552