Scientists at La Jolla Institute for Immunology (LJI) have made significant strides in developing a new therapy aimed at providing long-lasting relief for asthma patients, addressing the limitations of current treatments. A study recently published in the Journal of Allergy and Clinical Immunology suggests that this novel approach may not only offer relief for asthma sufferers but could also have broader applications for managing immune-related inflammatory conditions.
The breakthrough comes in the form of two therapeutic “cocktails” designed to prevent immune cells from overreacting to allergens, which are a key trigger for asthma attacks. The therapies target specific molecules—ICOSL, OX40L, and CD30L—that allow tissue-resident memory T cells to remain active and accumulate in high numbers within tissues. These T cells are responsible for triggering asthma attacks and sustaining inflammation. By blocking these molecules, the treatments prevent the T cells from causing further damage, offering the potential for long-term control of asthma symptoms.
In experiments using a mouse model of severe allergic asthma, researchers demonstrated the effectiveness of both therapy combinations. One cocktail combined ICOSL and OX40L inhibitors, while the other paired ICOSL with CD30L inhibitors. Both treatments successfully reduced tissue-resident memory T cells in the lungs, which are central to asthma exacerbations. The results were promising: the mice experienced prolonged protection from asthma attacks, even after repeated exposure to asthma triggers.
Dr. Gurupreet Sethi, the lead researcher and first author of the study, believes that these findings could lead to a significant advancement in asthma management. “By targeting these molecules in human patients, we could potentially help them develop lasting tolerance to allergens,” said Sethi. This breakthrough was made possible by funding from LJI’s Tullie and Rickey Families SPARK Awards for Innovations in Immunology, which support novel research through a philanthropic funding model.
The research builds upon earlier work by the Croft Lab, which identified the role of co-stimulatory molecules OX40L and CD30L in asthma attacks. Sethi’s team expanded on this by analyzing single-cell sequencing data from asthmatic human lungs, identifying significant variation among the T cells present. Some of these cells were more involved in lung inflammation and displayed diverse responses to the co-stimulatory molecules.
Sethi’s team focused on tissue-resident memory T cells, a subset of memory T cells that play a key role in the body’s long-term allergic responses. These T cells, while essential for remembering and responding to pathogens, contribute to chronic inflammation in asthma and other immune-related diseases. In their study, blocking both ICOSL and co-stimulatory molecules OX40L or CD30L led to a significant reduction in the number of tissue-resident memory T cells in the lungs—by up to 90%. This dramatic reduction provided lasting protection against asthma attacks in the mice, offering hope for the development of long-term asthma therapies.
The next phase of research will focus on finding ways to further reduce the remaining tissue-resident memory T cells. Sethi and his team are also working toward advancing both therapeutic combinations into clinical trials for human patients.
Beyond asthma, the research has broader implications for other autoimmune diseases. Researchers have identified the same tissue-resident memory T cells in conditions such as multiple sclerosis, atopic dermatitis, and inflammatory bowel disease. By limiting the presence of these cells, scientists believe it could be possible to reduce inflammation and prevent future flare-ups in a range of immune diseases.
Dr. Croft, co-author of the study, emphasized the potential impact of the findings: “If we can limit the number of memory T cells in tissues, we could prevent or minimize disease flare-ups. Currently, no approved treatments can achieve this, but our combination therapies might pave the way for more durable and effective treatments for several immune system diseases.”
The research represents a significant step forward in the fight against asthma and other inflammatory conditions, offering the potential for therapies that could alter the course of these diseases for good.
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