Epicutaneous immunotherapy on intact skin using a new delivery system in a murine model of allergy

Background Allergen‐specific immunotherapy, subcutaneous immunotherapy (SCIT) or oral, has been used for almost a century to redirect inappropriate immune responses in atopic patients. A new mode of administration through the intact skin [epicutaneous immunotherapy (EPIT)], using an original epicutaneous delivery system, may represent an alternative to these classical methods. Objective Proof of concept of efficacy of EPIT on intact skin in mice sensitized to aeroallergens or food allergens. Methods Mice were sensitized to pollen (n=18), house dust mite (HDM, n=24), ovalbumin (OVA, n=18) or peanut (n=18), and allocated to four groups: EPIT, SCIT, not treated (NT) and control. Specific Ig (sIg)E, sIgG1 and sIgG2a were monitored. After 8 weeks of treatment, plethysmography was performed after aerosol provocation with appropriate allergens. Results At the highest doses of methacholine, pause enhancement (Penh) values were significantly decreased in the EPIT group vs. the sensitized NT groups (7.5 vs. 12.3 – pollen, 7.6 vs. 8.9 – HDM, 11.5 vs. 14.5 – OVA, 7.6 vs. 12.8 – peanut, respectively) (P<0.05). With all the allergens tested, Penh values were similar in SCIT, EPIT and control. IgG2a for pollen, HDM, OVA and peanuts were significantly increased in the EPIT group vs. NT: 0.97 vs. 0.42 μg/mL, 2.5 vs. 0.46 μg/mL, 0.39 vs. 0.05 μg/mL and 15.0 vs. 5.5 μg/mL, respectively (P<0.05). There were no significant differences between EPIT and SCIT groups. The IgE/IgG2a ratio decreased significantly in the EPIT group for the four allergens from 70 to 58 (pollen), 175 to 26 (HDM), 5433 to 120 (OVA) and 49 to 6 (peanut), respectively (P<0.05). Conclusion In mice sensitized to the four allergens tested, EPIT was as efficacious as SCIT, considered as the reference immunotherapy. These first results have to be confirmed by clinical studies. Cite this as: L. Mondoulet, V. Dioszeghy, M. Ligouis, V. Dhelft, C. Dupont and P.‐H. Benhamou, Clinical & Experimental Allergy, 2010 (40) 659–667.     

Allergen immunotherapy with heat-killed Listeria monocytogenes alleviates peanut and food-induced anaphylaxis in dogs

BACKGROUND: Heat-killed Listeria monocytogenes (HKL) potently stimulates interferon (IFN)-gamma production in CD4 T-lymphocytes, and when used as adjuvant for immunotherapy, reduces immunoglobulin (Ig)E production and reverses established allergen-induced airway hyperreactivity (AHR) in a murine model of asthma. We asked if such treatment could decrease established peanut-induced anaphylaxis or cow's milk-induced food allergy in highly food-allergic dogs. METHODS: We therefore studied four 4-year-old atopic colony dogs extremely allergic to peanut (Group I), as well as five 7-year-old dogs very allergic to wheat, milk and other foods (Group II). All dogs experienced marked allergic symptoms, including vomiting and diarrhea on oral challenge with the relevant foods. The dogs were then vaccinated once subcutaneously with peanut or milk and wheat with HKL emulsified in incomplete Freund's adjuvant. RESULTS: Following vaccination of the allergic dogs with HKL and allergen, oral challenges with peanut (Group I) or milk (Group II) elicited only minor or no symptoms. In addition, skin test end-point titrations showed marked reductions for >10 weeks after treatment, and levels of Ara h 1-specific IgE in serum of peanut sensitive dogs, as demonstrated by immunoblotting, were greatly reduced by treatment with HKL plus peanut allergen. CONCLUSIONS: Thus, HKL plus allergen treatment markedly improved established food allergic responses in dogs, suggesting that such an immunotherapy strategy in humans might greatly improve individuals with food allergy and anaphylaxis.     

Food allergy immunotherapy: Oral immunotherapy and epicutaneous immunotherapy

IgE-mediated food allergy remains a significant and growing problem across the globe. Of the various treatment modalities, oral immunotherapy (OIT) and epicutaneous immunotherapy (EPIT) have been the best studied. Across various studies of OIT for egg, milk, and peanut allergy, strong levels of desensitization have been shown. With egg and peanut OIT, a limited remission, or sustained unresponsiveness (SU), has further been demonstrated. These advances have been further validated by successful phase 2 and phase 3 studies of peanut OIT. EPIT, using daily administrations of a proprietary patch, demonstrated efficacy as well as safety and tolerability in parallel phase 2 studies; however, its phase 3 study did not meet its primary efficacy outcome. Despite its good track record of desensitization, the safety and tolerability of OIT has remained a question. EPIT, on the other hand, has proven safe and tolerable; however, the adequacy of its desensitization has remained to be determined. As OIT and EPIT continue their march toward regulatory review, optimizations for immunotherapy and novel therapies continue to be developed providing hope for food allergy patients everywhere.     

Epicutaneous exposure to protein antigen and food allergy

BACKGROUND: The aetiology of food allergy remains unclear. Although failure to develop or breakdown in oral tolerance has been proposed, the existence of physiologic sensitization routes other than the gastrointestinal tract cannot be excluded. OBJECTIVE: The purpose of this study is to clarify whether or not exposure to allergen through the skin can promote food allergy. METHODS: BALB/c mice were shaved on the back, and a patch impregnated with 100 micro g of ovalbumin (OVA) was applied to the dorsal skin for a 1-week period and then removed. After three courses of sensitization, OVA-specific antibodies in sera were measured, and then mice were orally challenged with 50 mg of OVA. Anaphylactic symptoms, plasma histamine levels, and histology of intestines and lungs after oral challenge were examined. RESULTS: Epicutaneous (EC) sensitization of mice to OVA induced a high level of OVA-specific IgE. Subsequent oral challenge with OVA resulted in symptoms of systemic anaphylaxis with elevated levels of plasma histamine as well as histological changes in both intestines and lungs. In the presence of anti-IL-4 antibodies, EC sensitization failed to provoke an IgE response, but still induced a Th2-predominant cellular immune response in lungs after oral challenge. CONCLUSION: We demonstrated for the first time that food allergy can be induced by allergen exposure through the skin. Our results identify a novel role of EC sensitization in the pathogenesis of food allergy.     

Pretreatment with glycomacropeptide reduces allergen sensitization, alleviates immediate cutaneous hypersensitivity and protects from anaphylaxis

Allergic disorders are characterized by the involvement of allergen-specific immunoglobulin (Ig)E antibodies and T helper type 2 (Th2) cells. The search for new therapies for allergic diseases has been the primary focus of interest for many investigators in recent years. Glycomacropeptide (GMP) is a biologically active component of milk that exhibits a range of immunomodulatory functions. We examined whether oral administration of GMP could affect the development of allergic sensitization and the severity of immediate cutaneous hypersensitivity reactions and of anaphylaxis. Rats treated with or without GMP were ovalbumin (OVA)-sensitized and several indicators of allergy were evaluated. Pretreatment with GMP resulted in reduction of antigen-specific IgE titre in rats when sensitized with OVA. GMP administration also markedly suppressed the proliferative response of splenocytes to antigen and the production of interleukin (IL)-13 by splenocytes of sensitized animals. In addition, GMP pretreatment attenuated the intensity of the immediate cutaneous reaction induced by antigen and protected the sensitized rats from severe anaphylaxis. These data demonstrate, for the first time, that the administration of GMP prevents allergen sensitization and reduces the severity of the early-phase reaction induced by antigen in cutaneous hypersensitivity and in anaphylaxis. GMP may be used as a novel prophylactic agent for the control of allergic diseases.     

Epicutaneous peanut patch device for the treatment of peanut allergy

Introduction: Food allergy prevalence has increased in recent decades, which has mobilized efforts to develop treatment alternatives. Epicutaneous immunotherapy (EPIT) is a novel method that involves transdermal administration of peanut allergen with the objective to induce tolerance. Recent clinical trials have shown its efficacy at increasing the eliciting dose in children with a favorable safety profile.

Areas covered: This review covers the proposed mechanism of action of EPIT in murine models and humans, efficacy and safety data from clinical trials with peanut EPIT, and a discussion on its potential role in the future management of peanut allergy.

Expert opinion: With the recent completion of pivotal trials for peanut EPIT and upcoming marketing, the main question for clinicians and food allergic patients is how to define its role in the management of peanut allergy and how it compares to oral immunotherapy (OIT). Like OIT, EPIT seems to promote immunological tolerance over time. However, EPIT could lack the rapid mast-cell desensitization induced by the progressive intake of food in OIT, which explains differences in short-term outcomes and safety profiles. Head-to-head and long-term comparison of real-life efficacy with regards to sustained unresponsiveness will help define its place in the food allergy arsenal.