Food Allergy Diagnosis and Therapy

Where Are We Now?

Aleena Syed; Arunima Kohli1; Kari C Nadeau

Disclosures

Immunotherapy. 2013;5(9):931-944. 

In This Article

Treatment of FA: Current & Future Potential

There are several therapies currently under investigation for FA, some more promising than others. A summary of these therapies follows.

Nonfood-specific Immunotherapy

Nonspecific immunotherapies do not target a specific allergen and instead target general immune mechanisms. Advantages of nonspecific immunotherapies include the potential ability to desensitize an individual to multiple allergens at a time, as many food-allergic individuals have more than one allergy.[26]

One of the most promising nonspecific immunotherapies is a formulation of herbs used in traditional Chinese medicine, titled food allergy herbal formula (FAHF). Two different formulations have been studied. FAHF-2, the combination currently under study, is a simplification of FAHF-1, containing nine herbs instead of the 11 in FAHF-1. Both have been shown in mice to be effective in protecting against peanut-induced anaphylaxis in a mouse model of peanut allergy.[80,81] Promisingly, FAHF-2 was found to be effective in protecting against multiple allergic reactions in a mouse model with peanut, codfish and egg allergies.[82] Two Phase I trials for FAHF-2 have been conducted and found the formulation to be safe and tolerated; in the first, it was found that peripheral blood mononuclear cells treated with FAHF-2 in vitro produced decreased IL-5, and increased IFN-γ and IL-10.[83] The second was an extended Phase I trial, lasting 6 months; FAHF-2 was safe and tolerated, and subjects demonstrated a decreased basophil response.[84] A Phase II trial to assess safety, efficacy and immunomodulatory effects is currently underway.[201]

Another particularly promising therapy is anti-IgE therapy, specifically the use of the monoclonal anti-IgE antibody omalizumab. Omalizumab binds free IgE, therefore preventing degranulation of basophils and mast cells and attenuating Th2 cytokine production; it has also been found to reduce symptoms of IgE-mediated asthma.[85] A Phase II trial of the use of omalizumab in peanut-allergic patients has been performed. While the study was halted early due to safety concerns during the entry food challenge, primary end point analysis demonstrated an 80-fold increase in tolerated dose in omalizumab-treated patients versus placebo.[86] As omalizumab targets all IgE, it may also show some effectiveness in treating multiple allergies. Omalizumab also shows promise as an adjunctive therapy for other immunotherapies, as demonstrated by Nadeau et al. in their pilot study combining omalizumab therapy with milk OIT;[87] several trials building on this idea are currently underway.[202–204]

Given the notable differences in gut flora between food-allergic and nonallergic individuals,[24,25] the use of probiotics – "live microorganisms, which when administered in adequate amounts confer a health benefit on the host"[205] – for treatment and/or prevention of FA is currently under study. While promising results have been shown in mice, especially in the administration of probiotic bacteria transfected with IL-10 or IL-12,[88,89] probiotic trials in humans have, overall, been disappointing.[90] There is, however, growing promise that the Human Microbiome Project,[206] which seeks to deep-sequence 16S ribosomal subunits of bacterial RNA, may help in identifying targets for gut biota manipulation, leading to more targeted and promising therapies.[2]

Other nonspecific therapies include: the use of parasites, specifically the helminth Trichuris suis ova, which has been found in mice to protect against IgE sensitization and anaphylaxis[91] and in humans to modulate ulcerative colitis[92] and Crohn's disease,[93] and which is currently under investigation in a Phase I trial;[207] and the use of agonists of Toll-like receptor 9, stimulation of which induces systemic and mucosal Th1 responses, and which in mice have been found to protect against peanut-induced anaphylaxis, both during and post-sensitization.[94] Toll-like receptor 9 agonists may also show promise as adjunctive therapies.[95]

Food-specific Immunotherapy

Specific immunotherapies target specific allergens, and are particularly promising as monotherapies; multiallergen-specific therapies are less common, but are beginning to emerge.

SLIT involves the administration of micrograms or milligrams of food, which are held under the tongue for a period of time and then either spat out or swallowed.[96] SLIT is currently widely used in Europe to treat environmental allergies; while it is also used in this way in the USA, it is still considered experimental and lacks US FDA approval.[97] SLIT has been studied for use as immunotherapy for hazelnut,[98] milk,[99,48] peach[100] and peanut[101] allergies; multiple trials are ongoing.[208–210] Overall, SLIT has been found to increase the threshold of tolerated allergen, as well as allergen-specific IgG4, an indicator of tolerance. Various studies have also found increases in IL-10[98] and salivary-specific IgA,[101] as well as decreased skin reactivity[48,100] and IgE;[101] others have found increased[100] or unchanged IgE.[98,99] A major advantage of SLIT is its high safety profile; most reactions are limited to localized oropharyngeal symptoms.[102] The challenges of SLIT are a lack of dose standardization,[97] relatively small maximum doses and potential for developing new sensitizations to related allergens.[103] SLIT may be especially useful in combination with other therapies that allow desensitization to higher amounts of allergen, such as OIT; In addition, given its effectiveness in environmental allergen treatment, it may prove useful for treatment of oral allergy syndrome (OAS).

OIT is currently under investigation and involves the oral administration of small doses of a causal allergen over time, with gradual dose escalation. Rapid desensitization can be achieved through heightened dose escalation and has been found to be enhanced with the addition of anti-IgE antibodies.[85] Despite some success in desensitizing many subjects with persistent FAs, OIT is associated with significant safety risks. Initial dosing must be performed in a setting monitored by health professionals, as most reactions occur during initial dose escalation and can require epinephrine administration to mediate anaphylactic reactions.[104] Epinephrine, if administered expediently, can be life-saving, yet recent studies highlight severe underuse in emergency room settings.[105] Thus, to ensure safety, monitoring should be coupled with patient education on treating anaphylaxis should a reaction occur outside the clinical setting. Even with extensive precautions, OIT is not suitable for all subjects, and many trials report adverse reactions during treatment. In a study on egg OIT,[106] reactions accompanied 25% of all OIT doses given and nearly 13% of the OIT subject group stopped dosing due to allergic or anxiety reactions. Another study deemed cow's milk OIT "insufficiently safe" for 25% of participants based on their reaction severity.[107] Similar trends are seen in studies of peanut OIT with up to 18% of participants unable to cope with side effects.[108–113] Eosinophilic esophagitis, allergic inflammation of the esophagus, is a condition that has been linked to FA in children[114] and has been reported to occur during some OIT treatments.[114–116]

Several meta-analyses on immunotherapy, as reviewed by Sampson, show that while OIT can be beneficial, it is not currently recommended for routine use.[117–119] Moreover, the response to OIT may not be uniform in all subjects. Keet et al. followed patients for an average of 4.5 years after ending milk OIT and found a majority of subjects limiting milk consumption due to adverse symptoms, with two reactions severe enough to require epinephrine use. One participant passed a 16-g challenge without symptoms, but became reactive again at follow-up.[120] Larger, randomized trials are necessary to investigate cost–effectiveness, safety and long-term efficacy.

Retrospective analyses are being performed on study cohorts to identify potential factors that could predict the probability of an adverse reaction. Risk factors for reaction in cow's milk OIT include high sIgE, SPT wheal diameter and reaction severity during baseline OFC;[107] however, these parameters cannot be generalized for all allergens and OIT protocols. These data are based on individual studies and, as of yet, OIT has not been standardized, further complicating interstudy comparison. Improved specificity in diagnostic tools could allow clinicians to discern the likelihood and severity of a response during initial OIT dosing. These tools could also allow for the customization of the dosing regimen to improve both safety and efficacy.

Combining OIT with anti-IgE therapy has been suggested as a means of minimizing reactions during treatment. Prior studies have shown that monoclonal antibodies to IgE, such as omalizumab, can increase the threshold for reactivity to an allergen,[121] but do not significantly minimize the rate of adverse reaction. Anti-IgE functions by neutralizing unbound IgE and preventing interaction with IgE receptors on basophils and mast cells that would elicit an allergic response.[122] In a study from Bedoret et al., coupling milk OIT with omalizumab allowed for rapid dose escalation and resulted in nine out of ten subjects tolerating >8000 mg of milk in just 24 weeks.[79] In addition, all patients were able to complete 52 weeks of the study and continue with maintenance dosing to maintain desensitization. Subjects included in the study had high levels of milk-specific IgE, indicative of persistent allergy.[79] High levels of sIgE have been associated with a high likelihood of reaction,[56] suggesting that adjunct anti-IgE therapy with OIT would be well suited for more sensitive patients.

The studies described illustrate that patients undergoing OIT can become desensitized to food allergens; the potential to achieve long-term tolerance is still under investigation. Desensitization is a state of unresponsiveness to antigen while continually taking OIT doses. 'Tolerance' is considered when the antigenic food is removed from the diet for a period of time and, when reintroduced, still does not elicit an allergic response. Longitudinal studies are needed to determine the ideal dosing scheme to not only desensitize, but to also possibly tolerize patients. In a study by Burks et al., immune markers were studied that could differentiate patients who will achieve tolerance from those who will not. Increased levels of egg-specific IgG4 and small SPT wheal diameter were associated with passing an OFC, 4–6 weeks after discontinuing OIT.[106] Baseline characteristics may also be used to possibly determine the likelihood of developing tolerance. In studies by Jones et al. and Burks et al., and others, patients with lower peanut-specific IgE and smaller SPT before starting OIT were more likely to tolerate OFC after discontinuing OIT for 1 month.[108,123]

To date, OIT has not been shown to induce long-term tolerance, with studies extending for 2 years at most, and we should be careful before drawing any firm conclusions on its long-term effects.[119] Studying tolerant and nontolerant cohorts for extended time periods is necessary for exploring the possibility of inducing long-term tolerance.

The mechanisms involved in the development of desensitization and tolerance following OIT are still unclear, but appear to modulate the immune profile. Studies measuring immune parameters report changes in the number of Tregs.[124] Tregs are modulatory cells that play a crucial role in immune tolerance and help attenuate allergen-mediated responses through their suppressive function.[125] Increases in IgG4 production,[95] decreases in proinflammatory Th2-type cytokines and suppressed basophil activation[126] have all been associated with OIT and could be enhanced by suppressive Treg cytokines. The development of Tregs appears to be dose-dependent; low dosing results in the development of antigen-specific Tregs, while high-dose OIT results in T-cell effector anergy, but no Treg development.[79] In FA, antigen presentation occurs at the intestinal level, so the migration of Tregs, as well as the development of tolerogenic dendritic cells, is also being explored as a possible mechanism of induced oral tolerance.[127–131] Mechanistic understanding of induced tolerance may help us determine if Treg development or T-cell effector anergy is necessary for sustained unresponsiveness. These findings could help determine if slow or rapid dose escalation is optimal for achieving tolerance. In addition, mechanistic studies could aid in the development of diagnostic tools to measure OIT progress.

The mechanisms of specific immunotherapies such as OIT and SLIT are thought to be similar,[128] but variations in dosage may account for differences in the amount of antigen tolerated between therapies. Compared with OIT, SLIT is associated with localized, less severe systemic reactions. Having patients undergo SLIT followed-up by OIT could allow even hypersensitive patients to benefit from OIT. In a study performed by Wood's group, patients with milk allergy treated with SLIT followed by OIT allowed sensitive patients to undergo treatment and resulted in elevated levels of allergen tolerance compared with SLIT alone.[48] The greatest limitation of OIT is the high rate of adverse reactions experienced during treatment. Combining other treatments with OIT could minimize adverse reactions and expand accessibility. Nonspecific therapies such as anti-IgE monoclonal antibodies and antihistamines are also promising. Before OIT is ready for clinical use, it must be standardized and made safer.

Subcutaneous immunotherapy (SCIT) is the most common immunotherapy for environmental allergies. However, clinical trials testing the use of SCIT to treat peanut allergy found it to be very dangerous, with high rates of systemic reactions, and its use has since been discontinued.[132,133] At the same time, SCIT for some environmental pollens does show promise as a potential therapy for OAS, an IgE-mediated FA found in patients with pollen or ragweed and characterized by oral allergic reactions to fruits, with similarity to said pollens (e.g., birch and apple and birch and hazelnut).[134] Birch pollen SCIT has been found to decrease clinical sensitivity and skin reactivity to apple in some subjects, as well as to increase the tolerated quantity of apple and hazelnut in some OAS patients with birch allergy.[135]

Another orally administered immunotherapy is the use of extensively heated egg and milk. Individuals who outgrow cow's milk or egg allergies tend to be allergic to conformational IgE epitopes instead of linear epitopes;[136,137] these epitopes may be disrupted by extensive heating, as occurs in baking, and so many of these children tolerate consumption of baked milk or egg products.[138,139] Regular ingestion of baked milk products has been associated with accelerated resolution of cow's milk allergy in children,[140] suggesting complete avoidance is not the best path to take. This liberalization of the diet through the introduction of baked or heated allergens is associated not only with possible desensitization, but has also been shown to vastly improve patient quality of life by decreasing the anxiety associated with strict food avoidance.[141] One of the major advantages of this finding is that the use of baked milk or egg products in therapy is the ease with which it can be used in the home as well as the clinic, but it should be noted that, without proper monitoring and prior assessment of heat-treated protein tolerance, this can be extremely dangerous.

Epicutaneous immunotherapy (EPIT) involves the delivery of allergen via an epicutaneous patch containing solubilized allergen.[142] Peanut EPIT has been successful in mouse models;[143,144] to date, the only published human trial was a pilot study in children with cow's milk allergy.[142] The study found EPIT to be safe and well tolerated, with no significant change in IgE. At the same time, EPIT is relatively safe, presenting with mostly mild side effects and it is easy to administer.[142] Studies of peanut EPIT in humans are currently being conducted.[211]

Intralymphatic immunotherapy, in which allergen is delivered directly to the lymph node via injection, is currently being assessed for treatment of human environmental allergies (specifically grass pollen[145–147] and cat allergen with an MHC class II-targeting modification[148]). It has shown great promise, having much greater efficacy than SCIT in far fewer doses, inducing stronger immune responses without polarizing T-cell responses.[146,149,150] Its use in FA therapy has yet to be assessed, although it has been found effective in a mouse model of ovalbumin allergy,[146] and its efficacy in aeroallergen therapy suggests it is an avenue worth pursuing.

Other specific therapies modify the allergen proteins used to decrease the potential of reaction while still inducing tolerance.

Peptide immunotherapy involves the administration of a small fragment of the allergen that, while able to elicit a T-cell response, is too short to cross-link IgE on basophils and mast cells and thus does not induce anaphylaxis.[151] It has been shown to be effective for treating cat and bee venom allergies in humans,[152] and egg and peanut allergies in mouse models,[152,153] with mouse data suggesting induction of a Th1 shift and increased Treg markers.[153] The main issue with peptide immunotherapy is the development of the peptide fragments: while some progress has been made on peanut in humans and egg in mice,[152,154–156] it is hard to produce a validated vaccine due to the complexity of creating a stable combination of multiple peptides in one vaccine.[157] At the same time, as animal trials and aeroallergen studies in humans progress, it seems FA peptide immunotherapy trials in human are not far off.

IgE-binding sites of allergens can be modified via site-directed mutagenesis or alteration of tertiary protein structure, a process that has been studied for quite some time in human environmental allergy immunotherapy.[152,158] Modified, hypoallergenic allergens that have been synthesized include peanut (Ara h 1,2,3),[159] milk (casein),[160,161] fish (parvalbumin),[162] peach (Pru p 1)[163] and apple (Mal d 1).[164] Human trials have yet to be performed, but recombinant ovomucoid was found to decrease anaphylaxis scores and histamine responses, while increasing IFN-γ, suggesting a Th1 shift.[165,166] Another modification being assessed is the addition of sugar moieties to the allergen to mimic pathogens and drive the Th1 response. Pretreatment with mannosylated bovine serum albumin (BSA) in BSA-sensitized mice was associated with significantly reduced anaphylaxis scores and lower BSA-specific IgE levels, via induction of IL-10 expression in dendritic cells via a C-type lectin receptor.[167]

Bacterial adjuvants, such as heat-killed Listeria monocytogenes and heat-killed Escherichia coli,[168] when delivered with allergens, can skew the immune system to a Th1 response, as has been demonstrated in dog and mouse models of peanut allergy.[152] Phase I clinical trials to study the safety of rectal delivery of heat-killed E. coli and a mixture of modified Ara h 1, 2 and 3 are currently underway.[212]

Finally, gene therapy may provide new directions. Bacterial plasmid DNA can be used to deliver genes of allergens or of cytokines important to tolerance (e.g., TGF-β), both of which have been found to be effective in modulating allergic responses in mouse models,[169,170] although this seems to have a strain-specific effect in mice,[171] suggesting consideration of human genetic variability will be necessary. Targeting genes found to be associated with development of FA may also be a promising avenue for preventing FAs, especially as our knowledge of the human genome and ways to manipulate it increases. At the moment, however, such therapies remain far off.

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