Prevention of food allergy development and suppression of established food allergy by neutralization of thymic stromal lymphopoietin, IL-25, and IL-33.

BACKGROUND

Food allergy (FA) is an increasing problem that has no approved treatment. The pro-TH2 cytokines IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) are associated with FA, and mAbs to these cytokines are reported to suppress murine FA development.

OBJECTIVE

We sought to determine whether anti-pro-TH2 cytokine mAbs can block both FA maintenance and induction.

METHODS

IgE-mediated FA was induced in BALB/c mice by oral gavage with medium-chain triglycerides (MCTs) plus egg white (EW) and was characterized by increased numbers of lamina propria TH2 cells, mast cells, and eosinophils, shock (hypothermia), mast cell degranulation (increased serum mouse mast cell protease 1), increased serum IgG1 anti-EW and IgE levels, and increased IL-4 and IL-13 secretion after MCT/EW challenge. Mice were injected with anti-IL-25, IL-33 receptor, and/or TSLP mAbs before initial oral gavage with MCT/EW to suppress FA development; treatment with the same mAbs was initiated after FA development to suppress established FA.

RESULTS

Injection of an mAb to IL-25, IL-33 receptor, or TSLP strongly inhibited FA development. No single mAb to a pro-TH2 cytokine could suppress established FA, and optimal FA suppression required treatment with a cocktail of all 3 anti-pro-TH2 mAbs. Treatment with the 3-mAb cocktail during initial MCT/EW immunization induced EW tolerance.

CONCLUSIONS

All of the pro-TH2 cytokines are required to induce our model of FA, whereas any pro-TH2 cytokine can maintain established FA. Pro-TH2 cytokines prevent oral tolerance. Combined treatment with antagonists to all 3 pro-TH2 cytokines or with an inhibitor of pro-TH2 cytokine production might be able to suppress established human FA.