New Mouse Model Developed for Eosinophilic EsophagitisA study funded in part by NIAID reports the development of a new mouse model for eosinophilic esophagitis (EoE), an allergic inflammatory condition of the esophagus that, in many patients, is associated with food allergy. The data suggest that EoE is driven by a class of immune cells called basophils and a type of signaling molecule, or cytokine, called TSLP (thymic stromal lymphopoietin). Importantly, immunoglobulin E (IgE), the antibody associated with food allergy, is not required for EoE development.
Photomicrograph of EoE patient biopsy. Photo Credit: NIAID Laboratory of Allergic Diseases
BackgroundEoE is characterized by an overabundance of eosinophils, a type of immune cell, in the esophagus. This excessive immune response may cause inflammation and narrowing of the esophagus, which can lead to difficulty swallowing.
The underlying cause of EoE is not known. Because EoE is associated with food allergy, removing allergens from the diet may be an effective treatment for some patients, but not all cases of EoE are triggered by food. Studies using targeted therapy such as blocking IgE or a cytokine called IL-5 have had limited success. As a result, the current therapy for EoE involves potent, non-specific anti-inflammatory agents such as corticosteroids.
Results of StudyDavid Artis’ laboratory at the University of Pennsylvania developed a new mouse model for EoE that is triggered by food allergy. In response to food allergens, the mice developed elevated numbers of eosinophils in the esophagus and gastrointestinal tract, and with prolonged exposure, developed food impaction (food obstructing the esophagus)—all symptoms consistent with human EoE.
The researchers discovered that development of EoE-like disease is dependent on both TSLP and basophils. By either blocking TSLP activity or by depleting basophils, the scientists were able to alleviate the EoE-like disease in mice.
To see if TSLP and basophils were involved in human EoE, the researchers examined samples taken from EoE patients. They found elevated levels of TSLP and observed that higher numbers of basophils in the blood positively correlated with higher numbers of eosinophils.
The researchers also tested EoE patients for a variant in the TSLP gene that has been linked to increased TSLP production. They observed that the numbers of basophils in the blood were higher in patients with this marker, suggesting that patients with high levels of TSLP and basophils are predisposed to develop EoE after exposure to allergic triggers such as food. More research is needed, however, to confirm this relationship.
SignificanceThe investigators have identified two potential targets (TSLP and basophils) for the development of new and effective therapies for EoE. Furthermore, this study underscores the importance of identifying genetic markers and how changes in gene expression may contribute to disease progression in allergic diseases.
Next StepsMore work must be done in the new mouse model and in patients with EoE to assess the roles of TSLP and basophils, both separately and in combination with each other, and how they lead to elevated eosinophil numbers.
ReferenceNoti M, Wojno ED, Kim BS, Siracusa MC, Giacomin PR, Nair MG, Benitez AJ, Ruymann KR, Muir AB, Hill DA, Chikwava KR, Moghaddam AE, Sattentau QJ, Alex A, Zhou C, Yearley JH, Menard-Katcher P, Kubo M, Obata-Ninomiya K, Karasuyama H, Comeau MR, Brown-Whitehorn T, de Waal Malefyt R, Sleiman PM, Hakonarson H, Cianferoni A, Falk GW, Wang ML, Spergel JM, Artis D. Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis. Nature Medicine (2013)
Understanding Food Allergy (YouTube)