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"... By comparing mice prone to food allergies with ones who never seem to develop them, researchers discovered that molecules in the gut called leukotrienes play a pivotal role in the transport of potential allergens out of the stomach and into the bloodstream, where they can trigger an allergic reaction. ...
A drug called zileuton, which is already approved for treating asthma, blocks the synthesis of leukotrienes—and sure enough, when her team and another group of researchers gave it to mice, the animals were able to consume foods that they’re allergic to without the life-threatening reaction. ..."
From the editor's summary and abstract:
"Editor’s summary
Cysteinyl leukotrienes (CysLTs) are inflammatory mediators implicated in allergic responses, particularly asthma. Two studies examined the role of CysLTs in the development of anaphylaxis in response to ingested food allergens in mice. Hoyt et al. found that CysLTs promoted the transport of intact food allergens from the gut lumen into the tissue.
Mice that did not experience anaphylaxis had variants of DPEP1, an enzyme that metabolizes CysLTs, linked to augmented enzymatic activity. Batchel et al. found that when cells from the hematopoietic compartment could not synthesize CysLTs, mice had attenuated responses to ingested allergens. Mast cells within the intestinal epithelium could synthesize and respond to CysLTs. In both studies, blocking the synthesis of CysLTs using the drug zileuton before or concurrent with food-allergen exposure prevented the symptoms associated with anaphylaxis in mice ...
Structured Abstract
INTRODUCTION
Allergic reactions to food are mediated by cross-linking of preformed food-specific immunoglobulin E (IgE) antibodies bound to tissue mast cells upon allergen exposure. However, some people who have food-specific IgE do not have any allergic reaction to that food and are considered “sensitized tolerant.” How this population remains unresponsive to allergens is unclear, but understanding the underlying mechanisms could identify approaches for treating food allergy.
RATIONALE
To identify the genetic causes of a sensitized tolerant state, we studied an unexplained aspect of food allergy in mouse models. With rare exceptions, the commonly used C57BL/6 mouse strain demonstrates anaphylaxis to food allergens when challenged systemically, but not orally, despite robust IgE production, thus potentially modeling a sensitized tolerant state. ...
RESULTS
We found that oral anaphylaxis–resistant C57BL/6 mice have gut barriers that are impermeable to intact food allergens relative to susceptible strains such as C3H/HeJ even before allergic sensitization. ... Using a forward genetic screen of oral anaphylaxis, we identified a ... cysteinyl leukotriene (CysLT) lipid inflammatory molecule. Although CysLTs are important mediators of allergic responses, a mechanistic connection between CysLTs and food allergen transport is unknown. We found that oral anaphylaxis–susceptible mice had elevated CysLTs in the gut, suggesting impaired DPEP1 enzymatic activity. Indeed, blockade of DPEP1 with cilastatin enhanced allergen absorption in anaphylaxis-resistant mice. Conversely, inhibition of leukotriene synthesis with zileuton reduced allergen absorption and prevented anaphylaxis after oral challenge in susceptible mice. ..."
Cysteinyl leukotrienes stimulate gut absorption of food allergens to promote anaphylaxis in mice (no public access)
Intestinal mast cell–derived leukotrienes mediate the anaphylactic response to ingested antigens (no public access)
Tuning food allergen transport by gut epithelial cells to trigger anaphylaxis.
Intestinal mast cell differentiation highlights mediator requirements for oral anaphylaxis.
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