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New Asthma Therapies Show Promise for Long-term Relief
Current asthma treatments often fall short for many patients, failing to provide long-lasting protection against severe asthma attacks.
Recent research from scientists at the La Jolla Institute for Immunology (LJI) reveals an innovative therapeutic approach that could enhance the long-term management of asthma. Findings from this study, published in the Journal of Allergy and Clinical Immunology, indicate that this new method could not only offer sustained relief for asthma sufferers but may also mitigate immune inflammation more broadly.
Researchers have formulated two distinct therapeutic “cocktails” aimed at preventing immune cells from reacting excessively to allergens. These cocktails work by blocking specific molecules—ICOSL, OX40L, and CD30L—that enable tissue-resident memory T cells to thrive in sufficient numbers. Without these crucial molecules, T cells are less likely to provoke asthma attacks and avoid persisting to instigate future incidents.
Significantly, both formulations of the cocktails have proven effective in treating a mouse model exhibiting severe allergic asthma. The research indicates that either an ICOSL and OX40L inhibitor combination or an ICOSL and CD30L pairing can be utilized for treatment.
The researchers express optimism that the flexibility provided by these two treatment options could enable healthcare providers to address the diverse manifestations of allergic asthma in patients. “If we can effectively target these molecules in human patients, this could lead to long-lasting tolerance to allergens,” notes Gurupreet Sethi, Ph.D., the study’s lead author.
Professor Michael Croft, Ph.D., a senior author of the study and a member of LJI’s Center for Autoimmunity and Inflammation, emphasizes the broader implications of the research, suggesting that these cocktails may not only assist asthma patients but could also be relevant for treating other inflammatory and autoimmune diseases.
Identifying Key Players in Asthma Attacks
This investigation builds upon previous work conducted in 2022 by the Croft Lab, which demonstrated that simultaneously blocking OX40L and CD30L reduced asthma attacks in mice. However, Croft posited that other co-stimulatory molecules might also play a significant role in asthma pathophysiology.
The team utilized single-cell sequencing data to explore the variability or “heterogeneity” of T cells in human asthmatic lungs. Their findings revealed that not all T cells behaved similarly, with certain subsets contributing more significantly to lung inflammation.
With financial support from LJI’s Tullie and Rickey Families SPARK Awards for Innovations in Immunology, Sethi developed a mouse model that mimics the diverse T cell populations seen in humans with asthma. An essential focus of this investigation was the distinct subtypes of memory T cells, which are crucial for recognizing and responding to previous threats but can lead to chronic immune responses in asthma sufferers.
“Memory T cells in the lungs trigger an exaggerated response to allergens, which is a significant challenge for patients,” Sethi explains.
His research pinpointed a subset known as “tissue-resident memory T cells,” which are influenced by ICOSL. This molecule is also vital for the functioning of these T cells during asthma flare-ups.
When Sethi and his team explored inhibiting ICOSL alongside OX40L and CD30L, they observed that roughly 50 percent of tissue-resident memory T cells remained despite treatment with OX40L and CD30L inhibitors. In contrast, the use of combinations involving ICOSL resulted in only 10 to 20 percent of these T cells persisting in the lungs.
This substantial reduction in memory T cells translated to remarkable outcomes, as mice were shielded from asthma exacerbations for weeks, even after being exposed to known asthma triggers. The treatment effectively seemed to erase the immune system’s memory of the allergens causing asthma.
Future Directions: Targeting T Cells for Broader Applications
As the research progresses, Sethi aims to further investigate methods to reduce the remaining 20 percent of allergic tissue-resident memory T cells in the lungs. He also aspires to move both therapeutic cocktails into clinical trials with asthma patients.
The implications of these findings may extend well beyond asthma treatment. Croft points out that similar tissue-resident memory T cells have been observed in various diseases, including multiple sclerosis, atopic dermatitis, and inflammatory bowel disease.
“The goal is to limit the number of memory T cells that persist in affected tissues, which should, in turn, reduce the inflammatory response and potentially prevent future disease exacerbations. Currently, there are no approved therapies that accomplish this,” Croft states. “The combination treatments we have identified could lead to durable and effective therapies for a range of immune-mediated diseases.”
Additional contributors to the study include Ashmitaa Logandha Ramamoorthy Premlal and Ashu Chawla.
This research benefited from The Brenda and Dave Rickey Foundation’s support, which is channeled through The Tullie and Rickey Families SPARK Awards for Innovations in Immunology, along with other institutional contributions from the La Jolla Institute for Immunology.
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