Available online 27 September 2022, 104611

Long-term peanut allergen-specific IgE tolerance can be induced by peanut allergen administered with nuclear receptor FXR and PPARα agonists.

Downregulated peanut allergen specific IgE are detected by recombinant Ara h1, Ara h2, Ara h6 magnetic beads ELISA.

Tolerogenic BMDC exhibited downregulated SREBP-1c and upregulated SHP.

Ara h2 and suppressive cytokine DNA vaccine suppress Ara h2-specific IgE.

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.

immunotherapy

peanut allergy

nuclear receptors

IgE

long-term peanut allergen-specific IgE tolerance

magnetic beads

peanut allergen

ELISA

6-ethyl-CDCA (obeticholic acid)

bone marrow-derived dendritic cells

constitutively active nuclear erythroid factor 2

DC, dendritic cells

plaque for IgE-producing cells/ELISPOT

peroxisome proliferator-activated receptor

immune-suppressive response modifier

small heterodimer partner protein

sterol regulatory element-binding protein 1c

sustained unresponsiveness/tolerance

© 2022 Published by Elsevier Inc.