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New La Jolla Institute for Immunology study may point to a better way to ward off asthma triggers

At left is lung tissue of untreated mice; at right is lung tissue of mice treated with antibodies blocking OX40L and CD30L.
At left is lung tissue of untreated mice; at right is lung tissue of mice treated with antibodies blocking OX40L and CD30L.
(Courtesy of Gurupreet Sethi / La Jolla Institute for Immunology)

Every day, 10 Americans die from asthma. While quick-acting inhalers and medications can reduce inflammation during an asthma attack, people with asthma have few tools to prevent the next attack from coming.

Now researchers at La Jolla Institute for Immunology have discovered that blocking two immune molecules at the same time was key to preventing asthma attacks in a mouse model.

“We have found a way to block the acute asthmatic inflammatory response, and we saw a strong, long-lasting reduction in asthma exacerbations,” said Michael Croft, a professor at LJI and senior author of the study, published Nov. 5 in The Journal of Allergy and Clinical Immunology.

When a person with allergies encounters an asthma trigger, harmful T cells boost their numbers in the lungs and release molecules that cause
inflammation. The new study shows how to throw a wrench in that process.

For the study, the Croft lab focused on blocking OX40L and CD30L, molecules that can activate the T cells that drive inflammation in asthma.

Croft and his colleagues worked with a mouse model sensitive to house dust mites, a common allergy and asthma trigger. The scientists showed that blocking OX40L and CD30L at the same time could stop the expansion and accumulation of harmful T cells in the lungs during an allergen attack, and this then led to reduced inflammation.

“The combination of taking out the two sets ... allowed for a strong reduction in the number of those pathogenic T cells, whereas
only neutralizing either one had a relatively mild effect,” Croft said. “That was quite a significant finding.”

Blocking both OX40L and CD30L also reduced the number of pathogenic T cells that lingered in the lungs following an asthma
attack. Those “memory” T cells normally would drive inflammation when a person encounters an allergen again. Without OX40L and CD30L, very few of the harmful T cells stuck around in the lungs, and mice had a weaker response to house dust mites for weeks after the initial treatment, according to the study.

“This suggests we were diminishing the immune memory of the allergen,” Croft said.

The study comes several years after an ineffective clinical trial targeting OX40L. Previous research by the Croft lab and other researchers had suggested that blocking OX40L could reduce airway inflammation, yet a neutralizing antibody against OX40L did not have a beneficial effect in asthmatic patients with house dust mite or cat allergies.

“Why did it fail?” Croft said. “The new study supports the idea that simply blocking OX40L was not enough.”

The research sheds light on the complexity of the immune system and suggests that long-lasting therapy of inflammatory and autoimmune
diseases may require a multipronged approach, especially when trying to limit the number of pathogenic T cells that are the central
drivers of the diseases.

A combination therapeutic to block both molecules would be complicated to test (researchers would need to prove the safety of blocking each separately), but Croft thinks either dual antibodies or a “bi-specific” reagent could work to block OX40L and CD30L together in a single treatment.

Croft is now thinking of the next steps for his lab. Blocking OX40L and CD30L reduced memory T cells but didn’t eliminate all of them. Croft
thinks additional target molecules could be out there.

“We’re trying to understand what those molecules might be,” he said. ◆