Mucosal co-application of lactic acid bacteria and allergen induces counter-regulatory immune responses in a murine model of birch pollen allergy
Introduction
The prevalence of type I allergies has constantly increased within recent years [1], leading to the fact that presently up to 30% of children in industrialized countries suffer from symptoms such as allergic rhinoconjunctivits, allergic asthma or atopic dermatitis [2]. The development of type I allergy, characterized by a dominance of type 2 cytokines (IL-4, IL-5, IL-13) [3], has been linked to several factors, such as genetic predisposition [4] and the nature of the allergenic protein [5]. These factors, however, cannot solely explain the increase in prevalence of atopic diseases. Evidence is accumulating that “western life style”—which is associated with reduced microbial exposure due to high hygienic standards—significantly contributes to the constant increase of allergies [6], [7], [8], [9]. In this context recent studies showed that early childhood exposure to livestock on a farm and ingestion of unpasteurized milk are related with a lower incidence of atopic diseases [10], and furthermore that children living on a farm lose their allergic sensitization more frequently than other children [11].
Lactic acid bacteria (LAB) correspond to a large family of Gram (+) bacteria, of which given genera or species are important members of the indigenous gut microflora in both humans and animals. Dietary LAB strains are also broadly used for preparation of fermented foods and specific strains have been attributed probiotic, i.e. health-promoting properties [12], [13], [14]. In the last few years, the possible role of specific LAB strains in the prevention of allergic diseases has become more evident. In particular the relation between the composition of the intestinal flora and the prevalence of allergic diseases has been epidemiologically documented, showing that infants from countries with a high prevalence of allergy—such as Sweden or England—have a lower intestinal colonization with certain LAB strains than children from countries where allergic diseases are less prevalent, such as Estonia or Nigeria [15], [16], [17]. Moreover, it was recently demonstrated that oral administration of a particular LAB strain (Lactobacillus rhamnosus GG) led to reduced atopic dermatitis in children with a positive family history of type I allergy [18], indicating that LAB indeed can exert an anti-allergic effect.
Until now, specific immunotherapy (SIT) [19] is the treatment of choice against type I allergy, performed by repeated injections of increasing doses of allergen extracts. Even though the treatment is successful in many cases there are certain drawbacks, such as frequent injections and long duration, often leading to a low compliance of the patients. Furthermore, aluminium salts which are used as adjuvants in SIT are potent inducers of Th2 responses [20], which might reduce the efficacy of this treatment. Thus, there is increasing interest in improving immunotherapy by the use of Th1 promoting adjuvants [21] and the change to a less invasive route, such as vaccination via the mucosal route [22].
Using a mouse model of type I allergy to birch pollen [23], we have previously tested several mucosal adjuvants for their capacity to modulate an allergic immune response. In this respect, we have demonstrated that immunomodulation can be achieved by the use of mucosal adjuvants such as cholera toxin [23], cholera toxin subunit B [24], or certain bacterial components (CpG-motifs) [25]. In the present study, we tested the capacity of two LAB strains, Lactococcus lactis MG1363 (L. lactis, a dairy strain) and Lactobacillus plantarum NCIMB8826 (L. plantarum, a human isolate), to prevent or modulate allergic immune responses. At first, we analyzed the cytokine profile induced by each LAB strain in murine spleen cell cultures. Subsequent intranasal application of these bacteria co-applied with the major birch pollen allergen Bet v 1—prior or after sensitization with the allergen—indicates that such LAB strains are promising candidates for mucosal vaccination against type I allergies.
Section snippets
Animals
Female, 7-week-old BALB/c mice were obtained from Charles River (Sulzfeld, Germany). Each experimental group consisted of five mice. All experiments were approved by the Animal Experimentation Ethics Committee of the University of Vienna and the Ministry of Education, Science and Culture.
Bacterial strains and growth conditions
Two strains of LAB were used for in vitro stimulation of naive spleen cells of BALB/c mice, as well as for in vivo applications in the murine model of birch pollen allergy. L. lactis MG1363 [26], carrying a
Type 1 cytokines (Fig. 2)
High amounts of the Th1-promoting cytokine IL-12 were produced after stimulation with increasing numbers of formalin killed L. plantarum and L. lactis bacteria, in comparison to stimulation with the Gram (−) E. coli control strain. IL-12 levels were eight times higher after stimulation with L. lactis, and 16 times higher after stimulation with L. plantarum compared to the control strain. Consequently, significantly higher levels of IFN-γ were produced by spleen cells after stimulation with the
Discussion
Based on the assumption that a lack of counter-regulatory immune responses may influence the development of type I allergy, prophylactic and therapeutic strategies promoting the induction of allergen-specific Th1 responses have been suggested as a promising concept for treatment of Th2-biased hyperresponsiveness. Studies by Riedler et al., showing that early exposure to livestock and farm milk is associated with reduced atopy development, may favour the concept of prophylactically triggering
Acknowledgements
We wish to thank Mrs. H. Robin-de Safta and Mrs. Karin Baier for technical assistance, and Dr. M. Kundi from the Institute of Hygiene, University of Vienna, for statistical analysis of the data. This study has been carried out with financial support from the Commission of the European Communities, QLK1-2000-00340, “Oral delivery of vaccine and therapeutic products using non-pathogenic lactic acid bacteria (LABDEL)”, and was supported by the Institut Pasteur de Lille and the Austrian Science
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