LA JOLLA—New research from the La Jolla Institute for Immunology (LJI) has discovered that blocking two immune molecules simultaneously is key to preventing asthma attacks in a mouse model. A study reporting the data, entitled “Combination Blockade of OX40L and CD30L Inhibits Allergen-driven Memory Th2 Reactivity and Lung Inflammation,” was published in The Journal of Allergy and Clinical Immunology.
“We have found a way to block the acute asthmatic inflammatory response — and we saw a strong, long-lasting reduction in asthma exacerbations,” stated Michael Croft, Ph.D., professor at LJI and senior author of the study.
When a person with allergies encounters an asthma trigger, harmful T cells boost their numbers in the lungs and release inflammation-causing molecules. And while quick-acting inhalers and medications can reduce inflammation during an asthma attack, people with asthma have few ways to prevent the next attack.
The new study has shown that it’s possible to throw a wrench in the inflammation process.
For the study, the Croft Lab focused on blocking OX40L and CD30L, which are signaling proteins similar to tumor necrosis factor. These molecules are upregulated by allergens and can activate the harmful T cells that drive inflammation.
Croft and his colleagues worked with a mouse model sensitive to house dust mites — a very 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; this also led to reduced inflammation.
“The combination of taking out the two sets of signals allowed for a strong reduction in the number of those pathogenic T cells, whereas only neutralizing either one had a relatively mild effect,” Croft noted. “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. These “memory” T cells would normally drive inflammation when a person encountered an allergen again. But without OX40L and CD30L on the job, very few of these harmful T cells stuck around in the lungs, and mice had a weaker response to house dust mites for weeks after their initial treatment.
“This suggests we were diminishing the immune memory of the allergen,” Croft explained.
This study comes several years after an ineffective clinical trial which targeted OX40L alone. Previous research by the Croft lab and other researchers had suggested that blocking signaling from OX40L could reduce airway inflammation, yet a neutralizing antibody against OX40L did not have a beneficial effect in asthmatic patients with dust mite or cat allergies.
“Why did it fail?” Croft asked. “The new study supports the idea that simply blocking OX40L was not enough.”
“Similar to blocking OX40L … inhibiting CD30L alone had no significant effect on BAL [Bronchoalveolar lavage] cellularity, eosinophilia, or overall lung inflammation. In contrast, co-blocking OX40L and CD30L together resulted in a marked diminution of all parameters measured,” the article adds. “This included ~50% reduction in total BAL CD45+ infiltrates, including eosinophilia, and a comparable decrease in lung inflammation scored by histological examination of tissue sections.”
The research suggests that long-lasting therapy of inflammatory and autoimmune diseases could require a multi-pronged targeting approach.
“These latter results correlate with our finding that combined neutralization of OX40L and CD30L led to fewer effector memory CD4 T cells accumulating in the lungs but still allowed Treg to be generated,” says the study. “Interestingly, blocking both molecules was required to see a strong action on limiting the number of effector memory T cells that were generated, whereas blocking only one was sufficient for a good effect on reducing production of Th2 cytokines.”
A combination therapeutic to block both molecules would be complicated to test, and researchers would need to prove the safety of blocking each separately. However, Croft believes that either dual antibodies or a bi-specific reagent could work to block OX40L and CD30L signaling together in a single treatment.
Croft is looking forward to the next steps for his lab. Blocking both OX40L and CD30L reduced memory T cells, but didn't eliminate all of them — therefore Croft thinks additional target molecules could be out there.
“We're trying to understand what those molecules might be,” he concluded.
