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Targeted allergen-specific immunotherapy within the skin improves allergen delivery to induce desensitization to peanut

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Aim: Epicutaneous immunotherapy (EPIT) with peanut has been demonstrated to be safe but efficacy may be limited by allergen uptake through the skin barrier. To enhance allergen uptake into the skin, the authors used peanut-coated microneedles and compared them with EPIT in a peanut allergy mouse model. 

 

Methods: Sensitized mice were treated with peanut-coated microneedles or peanut-EPIT and then challenged with peanut to determine protection. 

 

Results: Treatment with peanut-coated microneedles was safe and showed enhanced desensitization to peanut compared with peanut-EPIT administered via a similar schedule. Protection was associated with reduced Th2 immune responses and mast cell accumulation in the intestine. 

 

Conclusion: Peanut-coated microneedles have the potential to present a safe method of improving allergen delivery for cutaneous immunotherapy.

Microneedle-Mediated Allergen-Specific Immunotherapy for the Treatment of Airway Allergy in Mice

 

Subcutaneous allergen-specific immunotherapy (SCIT) qualifies as a promising approach for the permanent cure of IgE-mediated airway allergies, which can often manifest into allergic rhinitis and other allergic respiratory diseases. SCIT entails repeated administration of a high allergen dose into the subcutaneous (sc) region using a hypodermic needle for many (3-5) years, which is inconvenient and painful and reduces patient compliance. To overcome these limitations, we hypothesized that microneedles (MNs), which are minimally invasive and painless, could provide a novel approach for allergen desensitization by depositing the allergen into the superficial layers of the skin. To test this hypothesis, we compared MNs and SCIT for allergen desensitization in a mouse model of ovalbumin (Ova)-induced airway allergy. Mice were first made allergic to Ova and then treated with MNs coated with Ova (with or without CpG as an adjuvant) or via SCIT-Ova + alum (subcutaneous Ova + alum injections) for comparison. Treatment with coated MNs significantly induced Ova-specific serum IgG antibodies in a manner comparable to SCIT-Ova + alum-treated group. To test the efficacy against allergen challenge, treated mice were challenged with Ova via the nasal route. Coated MNs with Ova and CpG (MN-Ova + CpG) considerably suppressed the airway inflammation in allergic mice, evidenced by downregulation of proinflammatory cytokines (IL-5 and IL-13), upregulation of anti-inflammatory cytokine IL-10, and activation of Ova-specific immune response in bronchoalveolar (BAL) fluid. The therapeutic capacity of MN-based allergy treatment was further validated by the reduction in eosinophil and mast cell infiltration in the lung tissues of mice treated with MN-Ova + CpG, and low deposition of mucus inside their lung bronchioles. Overall, coated MNs ameliorated the symptoms of airway allergy in mice similar to SCIT and could provide a novel means of painless allergen-specific immunotherapy.

Microneedles coated with peanut allergen enable desensitization of peanut sensitized mice

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The prevalence of peanut allergies has escalated over the last 20 years, yet there are no FDA approved treatments for peanut allergies. In this study we evaluated the potential of microneedles to deliver peanut protein extract (PE) into skin and assessed if the ensuing immune responses could desensitize mice that were sensitized to peanuts. Peanut sensitized mice were either treated through cutaneous immunotherapy using PE-coated microneedles or not treated, and then orally challenged with PE. After oral challenge, the clinical symptoms of peanut-induced anaphylaxis were significantly lower in the microneedle treated mice as compared to untreated mice, and this was accompanied by down-regulation of systemic anaphylaxis mediators such as histamine and mast cell protease-1 (MCPT-1) in the microneedles treated group. Overall, there was an up-regulation of Th1 cytokines (IL-2 and IFN-γ) as compared to Th2 cytokines (IL-4 and IL-5) in splenocyte culture supernatants of the microneedle treated group as compared to untreated group, suggesting that microneedles promoted immune modulation towards the Th1 pathway. Furthermore, mice treated with PE-coated microneedles were observed to retain integrity of their small intestine villi and had reduced eosinophilic infiltration as compared to the untreated but peanut sensitized mice, which further confirmed the desensitization capability of peanut cutaneous immunotherapy using coated microneedles. Thus, our current study represents a novel minimally invasive microneedle based cutaneous immunotherapy, which may provide a novel route of desensitization for the treatment of peanut allergies.

A comparative study of microneedle-based cutaneous immunization with other conventional routes to assess feasibility of microneedles for allergy immunotherapy

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Feasibility of microneedles (MNs) for cutaneous allergen specific immunotherapy (ASI) is demonstrated by comparing against currently practiced subcutaneous (SC) allergen immunotherapy, and the intramuscular (IM) and intraperitoneal (IP) routes. In Balb/c mice with ovalbumin (Ova, 25 μg) as the allergen MNs-Ova without alum induced anti-Ova IgG response comparable to IM but higher than SC and IP groups (250 μg alum was additionally used for SC, IM and IP groups). MNs-Ova induced higher anti-Ova IgG1 and IgG2a responses in comparison to other routes; however IgG2b and IgG3 responses were significantly lower than the IP group. As in SC group, anti-Ova IgE and IgA were low for MNs-Ova. Furthermore, MNs-Ova induced expression of IL-5, IL-13, IFN-γ and IL-1β cytokines in serum, but at significantly lower levels than other routes. Overall, MNs-Ova induced allergen-specific IgG antibodies, and activated the Th1 pathway (evidenced by higher IgG2a levels), suggesting their potential use for painless ASI.