Full length articleEffect of different helminth extracts on the development of asthma in mice: The influence of early-life exposure and the role of IL-10 response
Graphical Abstract
Introduction
Atopic asthma is the most common chronic inflammatory disease, resulting in high morbidity and important economic impact for families and health systems worldwide. Glucocorticoid is the most efficient anti-inflammatory treatment in persistent asthma so far (Szefler, 2011). However, its efficacy is restricted to established clinical disease and chronic use is necessary for disease control. Novel therapies with a preventive effect that could be initiated before allergic sensitization and disease expression have been searched worldwide (Holt and Sly, 2007).
Despite the great scientific advances in the understanding of immunology and risk factors of allergic diseases, the prevalence of asthma and allergic rhinitis has increased in developed countries over the last decades (Braman, 2006). Many studies have demonstrated contrasting prevalence between industrialized/urban and nonaffluent/rural populations (Alfven et al, 2006, Anonymous, 1998, Hagel et al, 1993, Von Ehrenstein et al, 2000, Yemaneberhan et al, 1997). Environmental factors play a pivotal role in these discrepancies (Heinrich et al, 1998, Williams et al, 1994). The hygiene hypothesis, proposed originally by Strachan in the end of the 1980s, postulated that infections and unhygienic contact with older siblings or through other exposures confer protection from the development of allergic illnesses (Strachan, 1989). This hypothesis has been considered immunologically plausible and infections remain the most important protective factor to the development of atopic diseases (Flohr et al, 2006, Strachan, 2000).
Epidemiologic studies have consistently demonstrated that different helminth infections are associated with reduced skin prick test responsiveness (Cooper et al, 2003, Flohr et al, 2006, van den Biggelaar et al, 2000). In asthma, human studies present more controversial results. Scrivener et al. demonstrated that African subjects with a higher prevalence of parasitic infections show less symptoms of asthma (Scrivener et al., 2001). Other study demonstrated that Schistosoma mansoni is correlated with low prevalence of asthma in infected teenagers and is inversely correlated with skin prick test in atopic subjects (Medeiros et al., 2003). On the other hand, Ascaris lumbricoides infection was associated with asthma (Leonardi-Bee et al, 2006, Lynch et al, 1997, Palmer et al, 2002). These controversial data suggest that parasitic infections may either predispose or protect against the development of asthma. Different helminths could trigger different immune responses, resulting in distinct effects on asthma. Indeed, the relationship between helminth infection and asthma is not clearly understood.
The immune response in helminth infections and allergy share many important features, such as T-helper type 2 (Th2) response (up-regulation of IL-4, IL-5 and IL-13), increased production of IgE, mast cell activation as well as eosinophilia. Infections could influence the allergic drive either through Th1/Th2 imbalance or regulatory T (T-reg) cell stimulation. Despite the immunological similarities between host response to endoparasitic infections and to external allergens, helminth-infected individuals appear to be protected from allergen sensitization, and it has been suggested that this is due to a protective immuno-modulatory network generated by parasite-induced T cells and their cytokines, particularly IL-10 up-regulation, ultimately leading to prevention of allergic tissue inflammation (Mahanty et al, 1996, van den Biggelaar et al, 2000).
Murine models have been useful in understanding the mechanisms of allergic asthma and helminth/atopy interactions. Many experimental studies have shown a consistently negative association between helminth exposure and allergic pulmonary response (Kitagaki et al, 2006, Lima et al, 2002, Pinto et al, 2004, Trujillo-Vargas et al, 2007, Wang et al, 2001). These studies have in common the analysis of the effect on allergic pulmonary response by one particular helminth. There is no previous experimental report comparing different helminths in the same study. The question whether all helminths have the same group-effect inhibitory mechanisms on asthma is not answered. Moreover, discussing treatment of diseases with parasites or their products is already a reality (Erb, 2009, Tilp et al, 2013) and some authors have advocated that the period in the development of allergic immune response – in which it is possible to modify an immune system atopic predisposition genetically inherited – is critical for primary prevention and new therapies for asthma (Holt and Sly, 2007). This period in life probably corresponds to the intra-uterine period and first months of life, characterized also by an immaturity of the immune system, particularly in relation to the T cells response. After complete maturity of immune system, most of the immunoregulatory therapies would probably not modify phenotypes already established. Thus, studies that determine the best moment for new therapy interventions for asthma that modify the immune response are necessary.
Hence, the aim of the present study is: (1) to analyze the effect of the exposure to different parasite extracts (Angiostrongylus cantonensis, Angiostrongilus costaricensis and Ascaris lumbricoides) on the development of the allergic pulmonary response in a murine model sensitized to OVA; (2) to evaluate in more detail the role of IL-10 in the mechanism of atopic asthma interaction with helminth exposure; and finally (3) to evaluate the characteristics of pulmonary allergic response in different moments of exposure to an extract of A. cantonensis in a murine model.
Section snippets
Processing and administration of the parasite extracts
Extracts of three different parasites were prepared: A. cantonensis, A. costaricensis and A. lumbricoides. A. costaricensis infective third-stage larvae (Santa Rosa–Brazil strain) were isolated from previously infected snail (Biomphalaria glabrata), as intermediate host. Infective third-stage larvae were obtained from the infected molluscan fibromuscular tissues after the snails had been minced and artificially digested with a 2 h incubation, at 37 °C, in 0.03% pepsin solution. Larvae were
Results
We evaluated the effect of exposure to a crude extract derived from adult worms of A. cantonensis, A. costaricensis and A. lumbricoides to inhibit OVA-induced pulmonary allergic response in mice, and the impact of an early exposure to the extract. The cellular lung eosinophilic response and the role of IL-10, IL-5 and INF-γ in this process were the main endpoints assessed. The mean returned volume of all the BAL performed was 0.68 ml and the mean cell viability was 100%. The mean percentage of
Discussion
In this study we have demonstrated that the exposure of mice to different helminth extracts (A. cantonensis and A. lumbricoides in BALB/c mice; A. costaricensis in C57BL/6 mice), particularly in early life (A. cantonensis in BALB/c mice), inhibits the eosinophilic pulmonary response induced by OVA. To the authors' knowledge, this is the first report analyzing the effect of different helminths on the development of allergic pulmonary response in mice, along with the temporal factor of exposure,
Ackowledgements
This study was funded by the Brazilian National Council for Scientific and Technological Development (CNPq) (478552/2006-8) agency.
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