Asthma remains a challenging condition to treat, with current therapies not providing relief for all patients and offering limited protection from potentially life-threatening attacks. However, new research from the La Jolla Institute for Immunology (LJI) suggests that a novel approach could provide lasting relief for asthma sufferers, potentially revolutionizing treatments for the condition.
A recent study published in the Journal of Allergy and Clinical Immunology introduces two promising therapeutic “cocktails” designed to prevent immune cells from overreacting to allergens, a key cause of asthma attacks. These cocktails target specific molecules — ICOSL, OX40L, and CD30L — which are responsible for maintaining specialized tissue-resident memory T cells in tissues. By blocking these molecules, the researchers found that they could prevent the T cells from triggering asthma attacks and reduce their persistence, which is a major contributor to chronic asthma flare-ups.
Two Potential Treatment Options for Asthma
The researchers demonstrated that either an ICOSL and OX40L inhibitor combination or an ICOSL and CD30L inhibitor combination successfully treated a mouse model of severe allergic asthma. These therapies effectively protected the mice from asthma exacerbations, even when they were exposed to triggers repeatedly, providing weeks of relief. The results indicate that these cocktails could offer long-lasting protection for asthma patients, potentially allowing doctors to tailor treatments based on the specific form of asthma each patient has.
Dr. Gurupreet Sethi, the study’s lead author and LJI instructor, highlighted the potential of these therapies, stating, “If we can target these molecules in human patients, they might be able to develop long-lasting tolerance to allergens.” This research is particularly promising not only for asthma treatment but also for dampening immune responses in other conditions involving inflammation.
Innovative Research Builds on Past Success
This breakthrough builds upon earlier work from the Croft Lab in 2022, which showed that blocking OX40L and CD30L molecules simultaneously could reduce asthma attacks in mice. However, the researchers suspected that additional molecules might play a role in the condition, prompting them to explore new avenues.
By analyzing single-cell sequencing data, the team identified significant variability, or “heterogeneity,” in the T cells from the lungs of asthmatic mice. Some of these T cells were more involved in lung inflammation than others, and they expressed receptors for OX40L and CD30L in different ways.
With funding from the Tullie and Rickey Families SPARK Awards for Innovations in Immunology, Dr. Sethi and his team developed a mouse model that mirrored the diversity of T cells found in human asthmatic lungs. This approach allowed them to identify a subset of memory T cells, known as tissue-resident memory T cells, which are responsible for prolonged allergic reactions in asthma sufferers.
A New Strategy for Treating Asthma
Dr. Sethi’s team discovered that ICOSL plays a pivotal role in the activity of these tissue-resident memory T cells. Blocking ICOSL in combination with OX40L or CD30L inhibitors led to a significant reduction in the number of these cells remaining in the lungs. While about 50 percent of tissue-resident memory T cells persisted after treatment with OX40L and CD30L inhibitors alone, the combination with ICOSL inhibitors further reduced this number to just 10 to 20 percent. This drastic reduction prevented asthma exacerbations for weeks in the treated mice, providing an effective and long-lasting solution to managing the disease.
Expanding the Impact Beyond Asthma
The implications of this research extend beyond asthma. As Dr. Michael Croft, senior author of the study, points out, tissue-resident memory T cells accumulate in a variety of autoimmune and inflammatory diseases, including multiple sclerosis, atopic dermatitis, and inflammatory bowel disease. By targeting these cells, the researchers believe that it may be possible to limit inflammatory responses and prevent disease flare-ups in these conditions as well.
“The idea is that if you can limit the number of memory T cells that remain in those tissues, you should be able to limit the extent of the inflammatory response, and you might be able to prevent future disease exacerbations,” explains Dr. Croft. “At present, no approved drug treatment has been able to do this. The combination therapies we have discovered could pave the way for durable and effective treatments for multiple immune system diseases.”
Next Steps and Clinical Trials
Dr. Sethi’s team plans to investigate ways to further reduce the remaining tissue-resident memory T cells in the lungs and move forward with clinical studies in human asthma patients. The combination therapies, which have already shown great promise in preclinical trials, could be the key to not only improving asthma care but also offering new hope for patients with other inflammatory and autoimmune conditions.
As the research progresses, the potential for these treatments to revolutionize the management of asthma and beyond becomes increasingly clear, offering new hope for millions of patients worldwide.
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