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-TH 2 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-TH 2 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 TH 2 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-TH 2 cytokine could suppress established FA, and optimal FA suppression required treatment with a cocktail of all 3 anti-pro-TH 2 mAbs. Treatment with the 3-mAb cocktail during initial MCT/EW immunization induced EW tolerance.

CONCLUSION: All of the pro-TH 2 cytokines are required to induce our model of FA, whereas any pro-TH 2 cytokine can maintain established FA. Pro-TH 2 cytokines prevent oral tolerance. Combined treatment with antagonists to all 3 pro-TH 2 cytokines or with an inhibitor of pro-TH 2 cytokine production might be able to suppress established human FA.