Elsevier

Vaccine

Volume 30, Issue 8, 14 February 2012, Pages 1437-1444
Vaccine

Oral administration of allergen extracts from mugwort pollen desensitizes specific allergen-induced allergy in mice

https://doi.org/10.1016/j.vaccine.2012.01.005Get rights and content

Abstract

Clinically, sublingual immunotherapy (SLIT) using allergen extracts effectively alleviates the symptoms of allergic rhinitis and asthma. We hypothesized that oral administration of a high-dose of allergen extracts imitates SLIT, which may prevent IgE-related responses in allergic diseases. In the present study, we investigated the effects of oral administration of allergen extracts from mugwort pollen (MP) on allergen-induced inflammation and airway hyperresponsiveness (AHR) in an allergic mouse model. After administration of MPdrop containing Art v 1 and Art v 4 extracts derived from MP specifically in MP-sensitized mice, the effects of MPdrop on AHR, inflammatory cell accumulation, cytokine production in the bronchoalveolar lavage fluid and lung tissue, and serum IgE and IgG levels were investigated. The results indicated that MPdrop not only prevented the AHR in response to methacholine in a dose-dependent manner but also significantly reduced the total serum and allergen-specific IgE levels. All of the maximal effects were achieved at a dose of 100 μg/(kg d) and were comparable to the effects of dexamethasone at a dose of 0.5 mg/(kg d). Furthermore, oral administration of MPdrop dose-dependently elevated allergen-specific serum IgG2a levels, reduced total and allergen-specific IgE levels and normalized the imbalance between the Th1 cytokine IL-12 and Th2 cytokines IL-4 and IL-5. Finally, oral administration of MPdrop significantly reduced goblet cell hyperplasia and eosinophilia in the MP-sensitized allergic mouse model. These data suggest that MPdrop effectively improves specific allergen-induced inflammation and AHR in MP-sensitized and -challenged mice and provides the rationale for clinical use of MPdrop in the specific allergen-induced asthma.

Highlights

Mugwort pollen (MP) extracts containing Art v 1 and Art v 3 as a specific allergen. ► Mugwort pollen (MP) extracts as a vaccine (MPdrop). ► Oral administration of MPdrop imitates clinical sublingual immunotherapy (SLIT). ► MPdrop effectively improves specific allergen-induced allergic asthma model in mice.

Introduction

Allergic diseases are the most common inflammatory diseases, and their prevalence and incidence have increased in many developed and developing countries [1]. Inhalation of allergens evokes deleterious immune and inflammatory responses, which further lead to allergic pathology and allergic symptoms [1]. A known risk factor for the development of atopic allergy is exposure and sensitization to the pollens. Pollens are important sources of outdoor allergens associated with asthma and other allergic disorders [2]. The overall prevalence of positive skin prick responses in Chinese individuals is 59.0% for Dermatophagoides farinae, 57.6% for Dermatophagoides pteronyssinus, 40.7% for Blomia tropicalis, 16.1% for American cockroach, 14.0% for dog, 11.5% for Blatella germanica, 11.3% for Artemisia vulgaris, 10.3% for cat, 6.5% for Ambrosia artemisiifolia, 6.3% for mixed mold I, 4.4% for mixed mold IV, 3.5% for mixed grass pollen and 2.2% for mixed tree pollen [3]. The most common and important outdoor aeroallergens are the pollens from Artemisia vulgaris (mugwort) and Ambrosia artemisiifolia (ragweed). To date, several clinically important allergens, such as Art v 1, Art v 2, Art v 3 and Art v 4, have been identified in crude mugwort extracts [4], [5], [6]. Recombinant Art v 1, Art v 2, Art v 3 and Art v 4 have been generated. They have been shown to exhibit allergic activity in humans and animals comparable with native products prepared from crude mugwort pollen (MP) extracts [6]. Because sensitivity to these allergens is present in 60–80% of patients with MP allergies, Art v 1 and Art v 3 could be valuable tools for the diagnosis and immunotherapy of allergic asthma and rhinitis caused by MP. Unlike symptomatic treatment, allergen-specific immunotherapy both improves symptoms and modifies the natural course of the disease in patients with allergic rhinoconjunctivitis, rhinitis and mild asthma [7], [8], [9], [10]. Because of traditional therapies, such as subcutaneous immunotherapy (SCIT), carry the risk of systemic reactions (e.g., anaphylaxis) [11], more convenient alternatives to subcutaneous injections are being developed to improve safety and compliance. Sublingual immunotherapy (SLIT) was developed for these purposes [10]. Many clinical studies have demonstrated that SLIT is a safe and clinically effective treatment in patients sensitive to pollens with rhinoconjunctivitis, rhinitis and asthma [8], [9], [10], [11], [12]. However, the detailed effects of MP extracts on the modulation of immunoresponse in allergy are not fully understood. Specifically, questions remain regarding how MP extracts affect IgG and IgE levels in specific allergen-induced asthma and whether MP extracts work by modulating the Th1- or Th2-biased allergic immune response; these questions merit further study [13], [14]. Established animal models were utilized to answer these questions [13], [14]. In the present study, we used MPdrop solution containing Art v 1 and Art v 3 extracts derived from mugwort (Artemisia vulgaris) pollen (MP) as an example of allergen extracts. MPdrop solution was orally administrated to MP-sensitized and -challenged mice. The effects of MPdrop on airway hyperresponsiveness (AHR), cytokine production, inflammatory cell accumulation in the bronchoalveolar lavage fluid (BALF) and lung tissue, and total and allergen-specific IgE and IgG2a levels in serum were investigated. Our data suggested that oral administration of MPdrop effectively improved specific allergen-induced inflammation and AHR in MP-sensitized mice and provide the rationale for clinical use of allergen extracts for the treatment of allergic diseases.

Section snippets

Animals

Female, 6–8-week-old BALB/c mice were purchased from Shanghai Slac Laboratory Animal Co. Ltd. (Certificate No. SCXK 2007-0005, Shanghai, China). All animals were housed in a room maintained at 23 ± 2 °C with 50 ± 10% humidity and a 12-h light, 12-h dark cycle (lights on from 8:00 A.M. to 8:00 P.M.). The animals were allowed free access to tap water and regular rodent chow. Rodent chow was withheld for 8 h prior to the experiments. All the animal care and handling procedures were approved by the

Allergen-induced airway hyperresponsiveness to methacholine

After subcutaneous sensitization and consecutive 7-d allergen challenge, lung resistance (RL) and dynamic lung compliance (Cdyn) were measured before and after provocation with different concentrations of Mch. Mice from the vehicle group developed a severe AHR in response to Mch, exhibiting significantly lower values in RL of PC100 (95% CI) and in Cdyn of PC25 (95% CI) compared with the control group (Fig. 2 and Table 1). However, MPdrop or Dex treatment significantly reduced the AHR in

Discussion

Sublingual immunotherapy (SLIT) is a methodology to administer allergen extracts in which the allergen is held under the tongue for a few minutes and then swallowed; this method is the so-called ‘sublingual-swallow’ [10], [12]. In fact, subjecting animals to SLIT is challenging. In the present study, we used a syringe to feed MPdrop solution into the mouths of mice for a few minutes until the solution was swallowed. Therefore, we considered a portion of the allergen have been absorbed by the

Acknowledgements

This work was supported by grants from the National Scientific Foundation of China (Nos. 81172880 and 30973542). We also thank Elsevier language editing services to revise the English writing of this paper.

Conflict of interest: The authors declare that there are no conflicts of interest.

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