Oral Immunotherapy (OIT): A Personalized Medicine

Oral Immunotherapy (OIT), a promising allergen-specific approach in the management of Food Allergies (FA), is based on the administration of increasing doses of the culprit food until reaching a maintenance dose. Each step should be adapted to the patient, and OIT should be considered an individualized treatment. Recent studies focused on the standardization and identification of novel biomarkers in order to correlate endotypes with phenotypes in the field of FA.


Introduction
Oral Immunotherapy (OIT), a promising allergen-specific approach in the management of Food Allergies (FA) [1], is based on the administration of increasing doses of the culprit food until reaching a maintenance dose, after which a regular intake of the specific food allergen is mandatory for "desensitizing" the patients to prevent exposure triggering an allergic reaction. While the main goal of the research is to induce sustained unresponsiveness or tolerance, OIT serves to introduce allergenic food into the normal diet, or in case of high-risk individuals, to introduce low doses in order to prevent severe reactions after accidental exposure [2].
In this regard, some researchers believe it is clinically and psychologically significant if a small amount of tolerance exists, enabling patients to tolerate accidental ingestion of the culprit food. Normally, FA is not just about tolerance or non-tolerance of the offending food. Recently, different phenotypes have been described, for example, patients who tolerate the allergenic food heated but are not able to tolerate the whole food uncooked. For this reason, OIT introduces new concepts such as the eliciting dose, the "matrix effect" (i.e., the complex interaction with other proteins, fats, and carbohydrates in the food matrix able to change protein allergenicity), and the way of processing foods. As a result, there is huge diversity among studies on the target food and the vehicle substance employed for OIT (i.e., some foods available commercially are used in their natural forms, while others use processed foods like defatted peanuts or dehydrated egg white), so the comparison among them could be difficult. Consequently, in the US, the Food and Drug Administration (FDA) has imposed standardization in terms of safety and quantification/identification of allergenic proteins. In fact, pharmaceutical-grade peanut flour is currently being subjected to phase 3 trials (AImmune) and is expected to be widely available in the coming years [3].
Another standardized drug for peanut OIT, called AR101, was studied in a phase 3 clinical trial that enrolled 551 patients with peanut allergy aged from 4 to 55 years [4].
Nonetheless, OIT should be considered an individualized treatment; hence its standardization in a general protocol represents a challenge for investigators and clinicians alike. Each step must be adapted to the patients' specific situation (i.e., infections, gastrointestinal disorders, drug assumption, exercise, adverse reactions during treatment). It is strongly recommended to conduct an oral food Despite the fact that life-threatening reactions have been observed in asthmatic teenagers with poor compliance [19,20], several studies show that even though mild adverse reactions are quite common with OIT, they tend to become less frequent and less severe over time [14].
While adverse reactions normally occur with dose escalation, they are also possible during maintenance therapy with doses that were previously well-tolerated, due to being unpredictable and at times triggered by cofactors like infections, exercise, and anxiety [21,22].
In particular, adverse reactions could be the cause of patients withdrawing in 3-20% of cases of milk OIT and 0-36% of cases of egg OIT [10,23].
In addition, most withdrawals are due to the occurrence of gastrointestinal symptoms and not to anaphylaxis, with reports of eosinophilic esophagitis (EoE) in 2.7% of patients subjected to milk, peanut, egg and wheat OIT [7,12,22,24,25]. In this review, we focused, in particular, on milk, egg, and peanut because they are the most frequently implicated in food allergy in children.

Quality of Life (QoL)
The variable impact that OIT can have on the quality of Life (QoL) probably depends on the QoL at baseline. There was great improvement in patients with impaired QoL at the beginning, whereas deterioration was observed in those with acceptable QoL at baseline [26]. Moreover, the number of doses tolerated by patients seems to be inversely associated with QoL. The more allergic patients who had frequent reactions during the first phase of OIT, even with a few tolerated doses, failed to show any improvement in their QoL, compared to a restricted diet. Conversely, for those children who completed the OIT protocols, an improved QoL was reported [27].

Immunologic Changes with OIT
During OIT, the T helper (Th)2/Th1 ratio is reduced and the T regulatory effector cells increase with the production of Interleukin 10 (IL-10) by the APCs (antigen-presenting cells) and the activation of immune cells which together with Transforming growth factor-beta (TGF-β) induce production of Immunoglobulin G4 (IgG4) and IgA. It is assumed that food-specific IgG4 during OIT could have an antigen-neutralizing effect and decreased basophil and mast cell responsiveness, with the suppression of IgE production. In allergen binding, both IgG4 and IgA compete with IgE, decreasing the allergen capture by basophils. This leads to a reduction in the amount of specific IgE, but also in the diversity of epitope recognition and altered affinity of IgE for antigens.
Decreased allergen-induced skin prick test (SPT) and basophil activation during the first few months of immunotherapy have been observed in OIT studies. However, a typical early increase in food-specific IgE levels has been demonstrated during the initial months of OIT. After 6 to 12 months of OIT, a transition has been observed from a Th2 predominant cytokine signature to a Th1-associated pattern, while immune suppression by T regulatory (T reg) cells and clonal anergy occur later during OIT. Syed et al. reported an increase in the function of antigen-specific CD4 + CD25 + Foxp3 + T Treg cells following OIT, corroborating the theory of active suppression of the immune response by food allergens [24,25,[28][29][30][31][32][33].

Sustained Unresponsiveness
Immunologic changes occurring during OIT-treatment seem to be temporary, revealing interindividual variability in immune suppression and clinical response. In egg OIT, from 71% to 90% of maintenance-phase patients retain desensitization after 1-6 years of follow-up [34][35][36][37][38]. In the literature, the length of follow-up reported in milk OIT ranges from 3 to 5.8 years. Desensitization to a full serving dose of cow milk (CM) equal to 200 mL is maintained in a range of between 31 and 100% of subjects [12,[39][40][41]. The avoidance period before retesting tolerance has been described as being as long as 1-4 months. One study on peanut allergy reported that 50% of patients (3/6 individuals) who passed an initial challenge test after a three-month avoidance diet following successful completion of OIT, had a positive second challenge test after the avoidance period was prolonged for a further three months [32]. Today, milk and peanut OIT are the most widely studied (Tables 1 and 2). There are very few publications on the egg (Table 3), other tree nuts (Table 4), wheat (Table 5), or fish OIT. achieved desensitization, and eight (p = 0.036) achieved two-weeks-SU to CM at 1 year from the start of OIT. Two years after the start of OIT, both the rate of desensitization and the rate of the two-week-SU in the OIT group significantly increased compared with the rates at one year (p = 0.025 and p = 0.008, respectively). There was a significant increase in the threshold in the pHF-pHF group (p = 0.048), but not in the eHFpHF group (p = 0.23). Among the participants with a severe allergy, whose baseline thresholds were <4 mL, there was a significant change in thresholds between baseline and at the end of the trial in the pHF-pHF group (p = 0.023).

Multiple Food OIT
A limit of OIT is represented by the fact that it is an allergen-specific approach, and most studies have been carried out on a single allergen, even though a great number of patients are sensitive to multiple allergens. For this reason, recent studies involving multiple foods have been described [89].
Moreover, in the case of tree nut allergy, cross-desensitization has been reported with the ingestion of only one type of nut thanks to the relevant cross-reactivity among tree nuts [83].

Desensitization Efficacy
A recent systematic meta-analysis of 31 clinical trials on food allergy [90] demonstrated the efficacy of desensitization, which entails an increase in the reaction threshold calculated as the food dose tolerated by the patient.

Personalized Medicine
It might be helpful to identify biomarkers associated with safe and successful OIT in order to select suitable subjects who are not expected to have reactions to OIT, screening out subjects in whom OIT could give rise to unnecessary risks.
While it is likely that the outcome of OIT depends on numerous factors, several individual characteristics could have a predictive value.
There is evidence that the following patients are at high risk for failing OIT "desensitization": 1.
with IgE binding to a boarder diversity of peptides; 2.
with high IgE-binding intensity to allergens: 3.
with the highest level of serum-specific IgE or the largest skin test response; 4.
with more severe reactions at low doses; 5.
with more severe asthma; 6.
with persistent allergy (desensitization could prove to be more effective in small children, suggesting that it is easier to achieve immune modulation when started at an early age) [10,43,58,59,91,92].
There is evidence indicating that the following patients as more likely to successfully complete OIT "desensitization", namely, those: 1.
who show a reduced skin prick test wheal size and an increase in specific IgG4-blocking antibodies after OIT to cow's milk, egg, and peanut [14,24], with the latter possibly being a biomarker for sustained unresponsiveness [91]; 3.
who show a tendency towards a decrease in the specific IgE levels.

Conclusions
Clinical and immunopathological studies on FA-OIT focus on novel biomarkers and therapies in order to correlate FA endotypes with clinical phenotypes and propose the best-personalized treatment for each patient with FA.
Moreover, more research is necessary for understanding whether a longer course of OIT could increase tolerance rates and whether OIT only accelerates desensitization in subjects who would, in any case, progress towards natural tolerance without any intervention.