OIT involves ingesting small, gradually increasing amounts of the allergen, typically in food or capsules. The goal is to desensitize the immune system to the allergen, allowing the patient to tolerate more significant amounts without experiencing severe reactions.

OIT had a significant positive effect in achieving tolerance, with a relative risk (RR) of 11.94 for peanut allergy compared to avoidance or placebo (7).

While OIT has shown promise in inducing desensitization and, in some cases, sustained unresponsiveness (SU), it is associated with a high incidence of adverse reactions, particularly gastrointestinal symptoms. These adverse events are usually mild to moderate but can impact the patient's quality of life and adherence to the therapy (11).

SLIT involves placing small doses of the allergen under the tongue, where it is absorbed into the bloodstream. This method is less invasive than OIT and generally has a better safety profile, with fewer and milder adverse reactions (12).

Despite its safer profile, SLIT may be less effective than OIT in inducing desensitization and SU.

EPIT involves the application of a patch containing the allergen to the skin. The allergen is absorbed through the skin, which has a high density of immune cells that can promote tolerance. EPIT is associated with mild local skin reactions, including itching and redness (13).

EPIT's non-invasive nature and favorable safety profile make it an attractive option, particularly for young children who may not tolerate OIT or SLIT well. However, its efficacy in inducing long-term tolerance is still under investigation.

Adjuvants, derived from the Latin word adjuvant—meaning “to help” -are usually added to vaccines to enhance their antigen-specific immune response and reduce some undesirable reactions (16). In allergy, an adjuvant is a substance or compound co-administered with the allergen extract and can increase allergen immunogenicity and modulate the immune response (17). Their role has, therefore, been investigated in OIT to improve the duration of tolerance, allow the administration of lower doses, and reduce treatment duration and side effects (18, 19). The ideal adjuvant should be biodegradable, stable, sustainable, non-toxic, and cost-effective, able to promote an appropriate immune response and combine optimal physiochemical properties with biological activity properties (17).

Several types of adjuvants have been evaluated for FA-AIT. However, in allergy, the preexisting T_H2 immune response is very robust, and establishing a protective immune reaction requires application schemes over 3–5 years to induce an immunomodulatory process. Although rates of successful desensitization are generally much high for SLIT and OIT, the effects are commonly lost after treatment cessation, and patients need to continue immunotherapy indefinitely to ensure ongoing tolerance (20).

Furthermore, safety concerns exist for food immunotherapy related to adverse allergic events (AEs). For EPIT and SLIT, AEs are generally limited, typically involving the treatment site, whereas OIT may provoke systemic reactions, including anaphylaxis requiring epinephrine use.

The optimal adjuvant should improve the safety and efficacy of FA-AIT by leading to faster relief of clinical symptoms and resulting in better patient adherence (21).

Studies have investigated bacterial therapies, such as probiotics, in treating allergic disorders, although challenges still need to be addressed due to study variability and inconsistent outcome measures. Probiotics significantly contribute to the production of Th1 cytokines, induce regulatory T cells (Tregs), and suppress Th2 pathways. Specifically, Lactobacillus strains facilitate the generation of semi-mature dendritic cells (DCs), enhance CD40 expression, inhibit IL-4 and IL-5, and promote IL-10 and TGF-β. They also boost local IgA production, which is essential for mucosal defenses (22, 23).

Research has explored the immunomodulatory effects of probiotics in promoting tolerance, showcasing their anti-inflammatory properties and ability to reduce reactive oxygen species (ROS) (24). Probiotics help balance Th1 and Th2 responses by regulating pro-inflammatory and anti-inflammatory cytokines and influencing gene expression during inflammation, which affects cell morphology and targeting. DCs, as antigen-presenting cells (APCs), are crucial for distinguishing between commensal bacteria and probiotics, with toll-like receptors (TLRs) playing a vital role in this process.

In food allergy treatment, the induction of Tregs has garnered significant interest. B regulatory cells (Bregs) exhibit immunosuppressive functions in various inflammatory diseases, including food allergies. Bregs produce cytokines such as IL-10, TGF-β, and TSP1, which repress T-cell mediated inflammation, enhance Treg function, induce tolerogenic DCs, and alter the phenotype of other local B cells. Bacterial signals can influence Breg phenotypes through interactions with short-chain fatty acids (SCFAs) like butyrate. Butyrate increases the production of the serotonin-derived metabolite 5-hydroxyindole-3-acetic acid (5-HIAA), which binds to the Aryl Hydrocarbon receptor (AhR). AhR acts as a transcriptional regulator for Bregs, boosting IL-10 production and suppressing pro-inflammatory cytokines such as TNFα and IL-6 (25).

Anti-immunoglobulin E (IgE) monoclonal antibody (mAb) was introduced as an adjunctive therapy to reduce OIT-related allergic reactions. Omalizumab, a humanized monoclonal antibody targeting the fragment crystallizable (Fc) portion of IgE antibodies, thereby preventing mast cell and basophil activation, has shown promising results in the treatment of food allergy, both as monotherapy and as an adjuvant to OIT. Numerous studies showed an increase in threshold dose for various food allergens after omalizumab treatment, limiting AEs such as urticaria and anaphylaxis (34, 35), laying the foundations for more rapid escalation of OIT dosing. Therefore, studies about omalizumab facilitating OIT confirm that omalizumab allows safer, more rapid desensitization from milk, although without sustained unresponsiveness (SU) (33, 35–38). Similarly, studies about omalizumab-facilitated peanut OIT demonstrated a more rapid desensitization with low rates of adverse reactions, providing sustained unresponsiveness after discontinuation (39–41). In the United States, 30% of children with food allergies react to multiple foods, and the worldwide prevalence of numerous food allergies reaches 2.4% (42). In this scenario, the ability to simultaneously treat multiple food allergies makes omalizumab attractive as an adjuvant for FA-AIT. Three studies demonstrated the efficacy of omalizumab in achieving multifood desensitization, which persisted even after discontinuation, although the durability of the effect varied depending on the food. Furthermore, biologics may enable some patients to undergo OIT by allowing better management of relative contraindications, such as uncontrolled asthma, eczema, urticaria, or eosinophilic esophagitis (43–45).

Dupilumab is a monoclonal antibody targeting the IL-4 receptor-α, thus inhibiting both IL-4 and IL-13 production. As omalizumab, dupilumab can succeed as an emerging adjuvant for OIT, and it is currently being studied for peanut allergy OIT (46).

Another novel approach to food allergy treatment is herbal therapy based on traditional Chinese medicine, which is thought to be effective in treating many diseases, including food allergies. Studies on peanut-allergic mice demonstrated that treatment with food allergy herbal formula 2 (FAHF-2) can reduce the frequency of adverse events, including anaphylaxis, down-regulating T_H2 responses, thus enhancing OIT desensitization (47, 48). However, the only study on humans revealed no clinical benefit, probably due to poor adherence (49).

Interferon-γ (IFN-γ) is a pro-inflammatory cytokine that usually protects cells from viral infections, that can counterbalance TH2 responses while promoting T_H1 reactions, reducing the production of IL-4 and IgE and inhibiting allergic sensitization (50, 51). Two studies evidenced successful sustained unresponsiveness or desensitization in food-allergic children treated with IFN-γ as an adjuvant to OIT (52, 53). Although the addition of IFN-γ seems to improve tolerability, studies are limited, and several side effects have been described related to IFN-γ administration to allergic patients.

Particle delivery systems are adjuvants that aim to facilitate the work of antigen-presenting cells by increasing the length of contact between the allergen and the patient's mucosa. Nanoparticles are delivery systems currently under research as new adjuvants in FA-AIT. They can provide an extra layer of protection for the allergen from degradation, therefore achieving high concentration at the site of action and increasing immunogenic properties. They can also prevent allergen recognition by IgE from basophils or mast cells, reducing allergenicity and, thus, the risk of adverse events (54). Given the promising immunomodulatory effects of CpG, two more recent studies evaluated the use of CpG-coated nanoparticles loaded with peanuts. CpG/peanut nanoparticles prevented anaphylaxis to oral peanut challenge, reduced Th2 cytokines, and increased IFN-γ levels in peanut-allergic mice (55). Recent studies have also investigated nanoparticles containing rapamycin, also known as sirolimus, an inhibitor of the mammalian target of the rapamycin (mTOR) pathway, known to induce antigen-specific immune tolerance. These studies proved the efficacy of rapamycin in attenuating allergic responses to food allergy (56, 57). Despite the potential intrinsic benefits of these systems, further studies to evaluate the safety profile of these compounds are still required to warrant the use of these emerging delivery systems as potential adjuvants in FA-AIT.

Common pathogens infecting the gastrointestinal (GI) tract have developed mechanisms to evade host immunity and cause infections. Vaccine vectors generated from those pathogens have been engineered to express different antigens, including food allergens. These vectors contain pathogen-associated molecular patterns (PAMPs), such as unmethylated CpG DNA, lipoproteins, and lipopolysaccharides that can activate the host immune system (58). However, creating modified heat-killed bacteria may be time-consuming and induce adverse events (gastroenteritis, sore throat, severe abdominal pain, and even anaphylaxis) while modifying pro-allergic T_H2 responses.

Purified microbial macromolecules, such as DNA, lipopeptides, and proteins, may induce similar beneficial immune responses as whole-cell bacteria without the associated disadvantages. Bacteria and virus express toll-like receptor ligands that are PAMPS, which activate the host immune system and may modulate pre-existing immune responses. Microbial macromolecules expressing Toll-like receptor-9 (TLR9) ligands, such as unmethylated CpG oligodeoxynucleotides (ODN), are potent inducers of T_H1 (59) and Treg (60) immunity and may determine a sustained decrease in IgE and IgG₁, as well as an increase in allergen-specific IgG_2a. Although TLR ligands (TLRL) can induce similar T_H1-associated immune responses as bacteria, such as Escherichia coli and Listeria monocytogenes, it is suggested that TLRL adjuvants only direct immune responses to the co-administered allergen, inducing persistent protection and enhancing safety. Despite these promising results, host immunity varies with age in response to TLR stimulation (61, 62), with neonates and infants being less responsive (63).