| Therapy | Mechanisms of action | Effects | Comments |
| Human data |
| Allergen-specific immunotherapy |
| Oral immunotherapy (OIT) | - Decreased skin test reactivity.
- Food-specific IgE increases during the first year of OIT then decreases.
- Increased food-specific IgG and IgA.
- FOXP3+ T cells are increased until 12 months and then decrease thereafter.
- Increased peanut-induced Treg function and hypomethylation of FOXP3.
- Decreased basophil reactivity to food allergen.
- Increased CD4+CD23high T cells.
- Increased IL-10, IL-5, IFN-gamma, and TNF-alpha and decreased IL-4 production by food-specific PBMCs.
- Genes in the apoptotic pathways are downregulated.
| - Sustained unresponsiveness (a surrogate term for oral food tolerance) or increased threshold dose of food for clinical reactions up to 6 months after stopping OIT can be attained in 30 to 50% after 3 to 5 years of OIT.
- Short-term success rate (a temporary state of desensitization) up to 85%, depending upon the food and treatment protocol.
| - Limited long-term follow-up data.
- Some patients experience recurrence of symptoms if food not ingested on daily basis.
- Generally local reactions with occasional serious systemic reactions and a high rate of gastrointestinal side effects (abdominal pain, nausea, vomiting) in up to 30% of subjects; 2.4 to 8% risk of treatment-emergent eosinophilic esophagitis.
- Convenience of home administration of maintenance doses but requires lifestyle modifications.
- The risk of an allergic reaction to a previously tolerated dose of food is associated with physical exertion within 1 to 2 hours after dosing, dosing on an empty stomach, dosing during menses, concurrent febrile illness, seasonal allergies, and suboptimally controlled asthma.
|
| Sublingual immunotherapy (SLIT) | - Serum food-specific IgG4 and total IL-10 increased in treated group.
| - Increased threshold dose on oral challenge. Efficacy lower than OIT and limited by the low dose of allergen that can be held under the tongue.
| - Systemic side effects rate 0.2% during rush build-up phase.
- One peanut SLIT study found a sustained unresponsiveness rate of 10% after 3 years of therapy, although 65% of the original 40 subjects did not continue therapy during the extended phase of this study.
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| Epicutaneous immunotherapy (EPIT) | - Serum food-specific IgE decreased; IgG1 and IgG4 increased; decreased reactivity of blood basophils and tissue mast cells.
| - Increased threshold dose on oral challenge; in 1 multicenter clinical trial, desensitization (defined as 10-fold increase in successfully consumed dose) was observed in 40% of treated subjects.
| - Low rate of systemic side effects; no gastrointestinal side effects.
- Up to 100% with local skin irritation under the patch; no long-term follow-up.
|
| Subcutaneous immunotherapy (SCIT) with chemically modified, aluminum hydroxide-adsorbed allergen | - Increased specific IgG and IgG4 levels for whole peanut, Ara h1, Ara h2, Ara h3, and Ara h6.
- Trend for decreased basophil reactivity.
| - Pilot study in 17 adults with peanut allergy reported good safety and tolerability.
| - A chemically modified, aluminum hydroxide adsorbed peanut extract for weekly subcutaneous administration is under investigation in subjects with peanut allergy (5 to 50 years) in a safety and tolerability randomized trial (NCT02991885).
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| Intradermal/intramuscular immunotherapy with LAMP-DNA vaccine | - LAMP-DNA vaccines use the natural biochemistry of LAMP to intersect with the process that APCs use to internalize, digest, and present exogenously derived antigens to the immune system as part of the lysosomal/MHC II complex and activate CD4+ helper T cells, as well as CD8+ cytotoxic T cells.
| - In peanut-allergic C3H/HeJ mice, intradermal injection of LAMP peanut vaccine attenuated allergic symptoms during peanut challenge, reduced peanut-specific IgE levels, and increased peanut-specific IgG2a levels compared with vector control.
| - There is an ongoing phase-I randomized trial to evaluate safety, tolerability, and immune response in adults allergic to peanut after receiving intradermal or intramuscular administration of a single multivalent peanut (Ara h1, h2, h3)-LAMP DNA plasmid vaccine (NCT02851277).
|
| Rectal immunotherapy with heat-killed bacteria and modified proteins | - Potentiation of Th1 and T regulatory cytokine responses.
| - Protection against peanut anaphylaxis in mice, lasting up to 10 weeks after treatment.
| - Concern for toxicity of bacterial adjuvants, excessive Th1 stimulation, and potential for autoimmunity.
- Heat-killed Escherichia coli expressing modified peanut allergens administered rectally caused allergic reactions in a subset of adults allergic to peanut in a phase-I clinical trial. No active studies.
|
| Allergen nonspecific |
| Monoclonal anti-IgE (omalizumab, talizumab) | - Binds to circulating IgE and prevents IgE deposition on mast cells and blocks degranulation.
| - Improves symptoms of asthma and allergic rhinitis; provides protection against peanut anaphylaxis in 75% of treated patients.
| - Subcutaneous at monthly intervals; unknown long-term consequences of IgE elimination. Food nonspecific. Not used as a monotherapy for food allergy but as a pretreatment for OIT to decrease adverse reactions during up-dosing.
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| Traditional Chinese Medicine (TCM) | - Downregulation of Th2 cytokines (IL-4, IL-5, IL-13), upregulation of Th1 cytokines (IFN-gamma, IL-12), decreased allergen specific-IgE, decreased T cell proliferation to peanut. Decreased basophil activation by food allergen.
| - Reverses allergic inflammation in the airways; protects mice from peanut anaphylaxis. No clinical protection in human studies when used as a monotherapy.
| - Oral, generally safe, and well tolerated; ongoing studies focus on identification of the crucial active herbal components in the multi-herb formulas and establishing optimal dosing. Ongoing multicenter clinical trial in combination with OIT and anti-IgE.
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| Animal data |
| Peptide immunotherapy | - Overlapping peptides (10 to 20 amino-acid long) that represent the entire sequence of allergen. Binding to mast cells eliminated; T cell responses preserved.
| - Protection against peanut anaphylaxis in mice; no human studies.
| - Improved safety profile compared with conventional immunotherapy; does not require identification of IgE-binding epitopes.
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| Engineered recombinant protein immunotherapy | - Binding to mast cells eliminated; T cell responses comparable with native peanut allergens.
| - Protection against peanut anaphylaxis in mice.
| - Improved safety profile compared with conventional immunotherapy; requires identification of IgE binding sites.
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| Immunotherapy with immunostimulatory sequences (ISS-ODN) | - Potent stimulation of Th1 cells via activation of APCs, natural killer cells, and B cells.
- Increased Th1 cytokines.
| - Protection against peanut sensitization in mice; no human studies.
| - Not shown to reverse established peanut allergy.
- Concern for excessive Th1 stimulation and potential for autoimmunity.
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| Human immunoglobulin Fc-Fc fusion protein | - Fusion protein crosslinks the high-affinity Fc-epsilon-RI and low-affinity Fc-gamma-RIIb receptors on mast cells and basophils.
| - Fusion protein inhibits degranulation of mast cells and basophils. No human studies.
| - A human gamma-allergen fusion protein, the Fc-Fel d 1 fusion protein inhibited Fel d 1-mediated degranulation in purified human basophils from cat-allergic patients and blocked the allergic responses in a mouse model. A similar approach can be used for food allergy.
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| Sugar-conjugated BSA | - Mannoside-conjugated BSA (Man51-BSA) targeted lamina propria dendritic cells expressing SIGNR-1 and promoted CD4+ type 1 Treg cells.
| - Mice sensitized with Man51-BSA were protected from anaphylaxis during an oral challenge with BSA and Man51-BSA. No human studies.
| - Sugar-modified food allergens might be used to induce oral tolerance by targeting SIGNR-1 and lamina propria dendritic cells.
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| Trichuris suis ova therapy | - Stimulation of IL-10 synthesis.
| - In a mouse model of food allergy protected against food IgE sensitization and anaphylaxis; no published human studies in food allergy.
| - Safe and afforded clinical improvement in Crohn disease and ulcerative colitis; no beneficial effect in adults with allergic rhinitis.
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