Oral Immunotherapy: Transforming Allergy Care

Oral immunotherapy (OIT) is revolutionizing allergy treatment by gradually exposing individuals to controlled amounts of allergens, retraining the immune system to reduce life-threatening reactions. As research refines its safety and effectiveness, understanding how OIT influences immune responses is key to improving treatment protocols and outcomes.

Immune Tolerance Pathways

OIT works by fostering immune tolerance through controlled allergen exposure. Regulatory T cells (Tregs) play a central role by suppressing allergen-specific immune activation and promoting long-term desensitization. Successful OIT is linked to an increase in FOXP3+ Tregs, which secrete anti-inflammatory cytokines like IL-10 and TGF-β (Palomares et al., Journal of Allergy and Clinical Immunology, 2021). These cytokines help shift the immune system away from an allergic phenotype, reducing IgE antibody production that drives hypersensitivity reactions.

Dendritic cells (DCs) also contribute by undergoing functional reprogramming in response to controlled allergen exposure. This tolerogenic shift includes increased expression of programmed death-ligand 1 (PD-L1) and reduced secretion of pro-inflammatory cytokines like IL-6 and TNF-α (Syed et al., Science Translational Medicine, 2014). These changes encourage Treg expansion while dampening effector T cell activity. Additionally, B cells produce allergen-specific IgG4 antibodies, which compete with IgE for allergen binding, reducing mast cell and basophil activation.

Long-term tolerance also involves epigenetic modifications, including DNA methylation and histone changes in immune-regulating genes (Ryan et al., Nature Communications, 2020). These alterations may explain why some individuals maintain tolerance after discontinuing therapy, while others require continued exposure. Identifying biomarkers that predict long-term success is crucial for optimizing OIT protocols.

Mucosal Immunology

The gastrointestinal mucosa plays a key role in allergen processing due to its vast surface area and specialized immune structures. Peyer’s patches and isolated lymphoid follicles within the gut-associated lymphoid tissue (GALT) facilitate allergen uptake through microfold (M) cells, which transport antigens to underlying dendritic cells. These cells then present allergens to naïve T cells, directing their differentiation toward a regulatory phenotype that supports tolerance.

Mucosal barrier integrity is critical for OIT success. Tight junction proteins such as occludin and zonula occludens-1 (ZO-1) regulate intestinal permeability, balancing controlled allergen exposure with preventing excessive penetration. Research shows transient barrier dysfunction can occur during dose escalation, contributing to early-phase side effects before adaptive reinforcement stabilizes barrier function (Katz et al., Journal of Allergy and Clinical Immunology, 2022).

Secretory IgA (sIgA) helps regulate mucosal immunity by binding allergens and limiting excessive immune activation. Elevated sIgA levels have been observed in successful OIT cases, suggesting a role in immune exclusion (Davis et al., Mucosal Immunology, 2021). Mucosal epithelial cells also contribute by releasing cytokines like thymic stromal lymphopoietin (TSLP) and transforming growth factor-beta (TGF-β), which promote tolerogenic immune responses.

Gut Microbiome Interactions

The gut microbiome influences allergen processing during OIT. Certain bacterial species, such as Bacteroides fragilis and Faecalibacterium prausnitzii, produce short-chain fatty acids (SCFAs) like butyrate and propionate, which help regulate immune responses. A study in Cell Reports Medicine (2023) found that patients with higher baseline levels of SCFA-producing bacteria showed improved desensitization rates, underscoring microbial composition’s role in OIT outcomes.

Diet also shapes microbiome function. Fiber-rich foods promote SCFA production, supporting a gut environment conducive to OIT, whereas processed diets with low fiber content reduce microbial diversity and increase pro-inflammatory bacteria. Researchers are exploring synbiotic supplementation—combining prebiotics with probiotics—to enhance microbial diversity and improve desensitization outcomes.

Fecal microbiota transplantation (FMT) is an experimental approach for modifying gut microbiota in allergic individuals. A small trial in The Journal of Clinical Investigation (2022) showed that microbiota transfers from individuals with low allergy susceptibility led to shifts in gut bacterial composition and improved allergen tolerance in some participants. While still in early research stages, this highlights the microbiome’s influence on immune responses.

Variations In Allergen-Specific Protocols

OIT protocols vary based on the allergen, with differences in dosing schedules, escalation strategies, and maintenance. Standardized approaches exist for common allergens like peanuts, milk, and eggs, but clinicians adjust protocols based on factors like patient age and allergy severity. Peanut OIT typically starts with microgram-level doses that gradually increase, whereas milk OIT often begins with higher doses due to differences in protein structure and allergenic potency.

Escalation rates also differ. Some protocols use rapid up-dosing to reach maintenance levels within months, while others extend escalation over a year or longer to minimize side effects. A JAMA Pediatrics (2022) study found that slower escalation for egg allergy reduced gastrointestinal symptoms and improved adherence. In contrast, accelerated protocols may be necessary for individuals at high risk of accidental exposure.