Current asthma treatments often fail to provide lasting relief, leaving patients vulnerable to potentially deadly asthma attacks. However, a new breakthrough therapy developed by scientists at La Jolla Institute for Immunology (LJI) could change this by offering long-term relief for people suffering from asthma and possibly other immune-related diseases.
Published in the Journal of Allergy and Clinical Immunology, the study introduces two innovative therapeutic “cocktails” that could prevent immune cells from overreacting to allergens, thus offering sustained asthma relief. These cocktails target key molecules—ICOSL, OX40L, and CD30L—that are crucial in maintaining tissue-resident memory T cells (TRM) in tissues. These specialized cells are responsible for triggering asthma attacks and fueling future exacerbations.
The study, led by LJI Instructor Gurupreet Sethi, Ph.D., demonstrated that by inhibiting these molecules, the researchers could reduce the number of memory T cells in lung tissues, preventing asthma attacks in a mouse model of severe allergic asthma. The research builds on earlier findings, which suggested that blocking OX40L and CD30L could alleviate asthma symptoms in mice. Sethi’s team took this further by identifying additional co-stimulatory molecules, including ICOSL, which also plays a significant role in the persistence of asthma-triggering T cells.
“The breakthrough in this study is that we’ve found two cocktails that could help different forms of allergic asthma,” said Sethi. “If we can target these molecules in human patients, they might be able to develop long-lasting tolerance to allergens, reducing the need for constant medication.”
The researchers tested their two combinations of inhibitors on mice: one combining ICOSL and OX40L inhibitors, and another with ICOSL and CD30L inhibitors. Both approaches showed promise. After treatment, only 10-20% of tissue-resident memory T cells remained in the lungs, compared to the 50% seen when other treatments were used. This sharp reduction in allergenic memory T cells led to long-lasting protection against asthma exacerbations—even when mice were repeatedly exposed to asthma triggers.
While the focus of this study is on asthma, the findings have broader implications for treating other immune system diseases. Sethi’s research suggests that tissue-resident memory T cells also accumulate in other inflammatory diseases, such as multiple sclerosis, atopic dermatitis, and inflammatory bowel disease. By reducing the number of these cells in affected tissues, the therapeutic cocktails could potentially prevent future flare-ups in a wide range of conditions.
“The combination therapies we’ve discovered could pave the way for more durable treatments for several immune system diseases,” said LJI’s senior scientist, Dr. Croft. “We believe that by limiting memory T cells in key tissues, we can reduce the inflammatory response and prevent disease exacerbations, a breakthrough that no approved treatment has yet achieved.”
Moving forward, Sethi plans to investigate methods for further reducing the remaining T cells in the lungs and hopes to bring these cocktail therapies into clinical studies for asthma patients. The researchers also anticipate that their approach could eventually be adapted to treat other chronic immune disorders, providing a new avenue for managing a variety of conditions that are currently difficult to treat.
With continued support from LJI’s Tullie and Rickey Families SPARK Awards for Innovations in Immunology, the study offers new hope for patients seeking long-term relief from asthma and other autoimmune diseases.
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