Suppression of established food allergy by a combination of anti-TSLP, anti-IL-33, and anti-IL-25 monoclonal antibodies.

Food ingestion generally induces antigen (Ag)-specific tolerance rather than immunity. In contrast, we recently reported (JACI, 131:442–50, 2013) that Ag-specific, IgE-mediated food allergy (FA) can be induced when a protein Ag is repeatedly ingested with a widely used nutrient, medium chain triglycerides (MCT), without any additional sensitization. Mice that have been repeatedly inoculated orally with MCT plus egg white (EW) develop a Th2 cytokine and an IgE response as well as shock (hypothermia) following oral EW + MCT challenge. Because MCT ingestion induces increased intestinal epithelial cell expression of the pro-Th2 cytokines TSLP, IL-25 and IL-33, we investigated the importance of these cytokines in establishing and maintaining FA. We found that treatment with neutralizing mAbs to any of the pro-Th2 cytokines could suppress MCT + EW-induced FA development, with aTSLP mAb causing near-total suppression and aIL-25 and aIL-33 each causing considerable suppression. In contrast, treatment with aTSLP mAb, by itself, had little effect on established FA to EW. Treatment of established FA with combinations of mAbs to any two pro-Th2 cytokines had a partial suppressive effect, with the combination of aTSLP + aIL-33 being most suppressive. Simultaneous treatment with mAbs to all three pro-Th2 cytokines caused complete loss of the hypothermia response to EW + MCT challenge and considerably reduced IL-4, IL-13, IgE, and mouse mast cell protease 1 responses. Thus, all three pro-Th2 cytokines are essential for FA induction, but these cytokines are somewhat redundant for FA maintenance in our model. These results provide a better understanding of the FA mechanisms and lead to the development of novel therapies.