Credit: MasterPhoto-DK (CC BY 2.0 https://creativecommons.org/licenses/by/2.0/deed.en)
Two teams of scientists have prevented anaphylaxis in mice with an US FDA-approved asthma drug. The drug, Zileuton, temporarily shields allergic mice from allergens they have ingested by blocking a newly discovered anaphylactic pathway in the gut before it activates.
The first study, published in the journal Science, revealed that mice naturally resistant to oral food-induced anaphylaxis had mutations in a gene which produces an enzyme called dipeptidase 1 (DPEP1).
DPEP1 breaks down the inflammatory lipid called cysteinyl leukotriene D4 (LTD4).
“Mice resistant to anaphylaxis had a more active version of DPEP1, allowing them to degrade LTD4 more efficiently in the small intestine,” the authors of the study write. “Susceptible mice had less active DPEP1, leading to higher LTD4 levels.”
Further experiments showed that LTD4 promotes the transport of allergens across the gut epithelium (barrier) and into the tissue and circulation where they trigger anaphylaxis.
Existing asthma drugs including Zileuton prevent leukotrienes like LTD4 from being produced.
The researchers found that when allergic mice were fed peanut extract shortly after Zileuton, 95% of them showed almost no symptoms of anaphylaxis.
“The treatment reversed their risk from 95% susceptible to 95% protected,” says co-senior author Dr Adam Williams, an associate professor of medicine (allergy and immunology) at Northwestern University in the US.
According to co-senior author Dr Stephanie Eisenbarth, director of the Center for Human Immunobiology at Northwestern, it was “shocking how well Zileuton worked”.
The new findings help explain a long-standing puzzle in allergy medicine: why some individuals can eat the food they are allergic to without having a symptomatic reaction.
“Let’s say you’re told you’re allergic to peanuts based on a blood test, but you’ve eaten peanuts your whole life without any problems. This pathway we discovered may be one explanation for why some of those people are protected,” Eisenbarth says.
This has been a challenge for clinicians and a source of stress for patients because current diagnostic tests only estimate allergy risk, not tolerance, she adds.
“Our findings open a whole new area for future research into how people develop food allergies in the first place, and why some react while others don’t.”
Study authors Drs. Stephanie Eisenbarth and Adam Williams weighing peanuts used in food allergy testing in their lab. Credit: Northwestern University
The prevalence of food allergy has increased in recent decades. Australia has the highest, with 10% of infants allergic to one or more foods.
According to the Australasian Society of Clinical Immunology and Allergy (ASCIA), the most common triggers of food allergy in Australia and New Zealand are egg, cow’s milk (dairy), peanut, tree nuts, sesame, soy, wheat, fish and other seafood.
But ASCIA notes that almost any food can cause an allergic reaction.
The most severe type, anaphylaxis, occurs when food antigens enter the bloodstream and activate immunoglobulin E (IgE)-primed mast cells – inflammation-mediating immune cells – throughout the body.
The resulting reaction is systemic and potentially life-threatening, narrowing of the airways and causing circulatory failure.
A second study published in Science independently discovered that cysteinyl leukotrienes (CysLT) are important drivers of oral anaphylaxis in mice.
They investigated the role of mast cells within the intestine and found they produce CysLT in response to allergens. This promotes the expansion of mast cells in the gut’s mucosa and stimulates acute sensitisation to allergens.
“Notably, in both studies, the CysLT synthesis inhibitor, Zileuton, attenuated orally induced anaphylaxis but had no effect on anaphylaxis when the allergen was parenterally administered through intravenous or intraperitoneal routes,” Assistant Professor Tamara Haque and Professor Mark Kaplan from Indiana University in the US, write in a related Perspective.
“Because … [both studies] show that Zileuton can inhibit orally induced anaphylaxis, future translational studies are warranted that examine the effectiveness of Zileuton in preventing anaphylactic food allergic reactions in humans.”
Williams and Eisenbarth’s team launched a small early-stage clinical trial to test whether Zileuton is as effective at blocking anaphylaxis in humans last month.