Long-term IgE immunological tolerance to peanut allergens: An alternative to Noon’s daily desensitization paradigm

Abstract

Herein, we show that profound afferent long-term peanut-allergen-specific IgE immunological tolerance for 3 to 9 months induced sustained unresponsiveness (SU) in naïve or peanut-sensitized rodents after peanut allergen immunization. Rodents were vaccinated sublingually with a peanut allergen extract or recombinant peanut allergen in chenodeoxycholate (CDCA), a fanesoid X receptor (FXR, NR1H4) agonist that downregulates SREBP-1c (sterol regulatory element binding protein-1c) and upregulates SHP in bone marrow-derived tolerogenic dendritic cells (DCs). Approximately 90 ∼ 95 % of the total circulating PE-potentiated IgE and Ara h1, Ara h 2, and Ara h 6 peanut allergen-specific IgE responses were suppressed by recombinant peanut allergen-conjugated solid magnetic beads (sensitivity of 0.2 IU/ml). In contrast, peanut allergen-specific IgG production was not affected. Similarly, oleoylethanolamine (OEA), a peroxisome proliferator-activator receptor alpha (PPARα) agonist, and GW9662, a PPARγ antagonist, induced long-term peanut-specific IgE tolerance when administered via the sublingual, oral or i.p. route. Prophylactic Ara h2 DNA immunization with caNRF2 and IL-35 coexpression induced Ara h2 IgE tolerance. In summary, peanut allergen vaccination with select natural molecular ligands of nuclear receptors induced long-term peanut allergen-specific IgE tolerance via the afferent limb, which indicates that vaccination is an immune tolerance-promoting strategy that is effective at the DC level and that differs from Noon’s daily desensitization program, which is effective at the mast cell level.