Intranasal Coadministration of Live Lactococci Producing Interleukin-12 and a Major Cow's Milk Allergen Inhibits Allergic Reaction in Mice

Abstract

The Th1/Th2 balance deregulation toward a Th2 immune response plays a central role in allergy. We previously demonstrated that administration of recombinant Lactococcus lactis strains expressing bovine ␤-lactoglobulin (BLG), a major cow's milk allergen, partially prevents mice from sensitization. In the present study, we aimed to improve this preventive effect by coadministration of L. lactis BLG and a second recombinant L. lactis strain producing biologically active interleukin-12 (IL-12). This L. lactis strain producing IL-12 was previously used to enhance the Food allergies, i.e., immediate-type, immunoglobulin E (IgE)-mediated immune responses, affect 2 to 2.5% of the general populations of Western countries (22,24,25). It results from the activation of the Th2-type helper lymphocytes. In mice, this response is mainly characterized by the production of interleukin-4 (IL-4) and IL-13, which induce the production of IgE and IgG1, and of IL-5, which attracts eosinophils. In contrast, the Th1 response is characterized by the induction of gamma interferon (IFN-␥) and IL-2 production and the stimulation of cellular immunity. Th1 and Th2 cells regulate their own development via the cytokines produced: IFN-␥ suppresses Th2-cell proliferation and promotes Th1-cell proliferation, whereas IL-4 promotes additional Th2-cell proliferation and inhibits Th1-cell development (39,43,45).A recent study suggests that an early allergen-specific induction of Th1 cells before allergy sensitization could not efficiently prevent the development of atopic disorders: Th1 priming was abolished in the presence of allergen-specific Th2 cells, whereas Th1 cells could not inhibit subsequent priming of Th2 cells (58). The use of adjuvants that increase the proliferation of Th1 cells and that render them more efficient in inhibiting Th2 cells would therefore be of great interest in the management of allergic diseases. These observations prompted us to explore the adjuvant effect of IL-12 in a mouse model of allergic reaction to bovine ␤-lactoglobulin (BLG), a major milk allergen (2). IL-12 is a heterodimeric cytokine produced by antigen-presenting cells that promotes the development of naïve Th cells into Th1 effector cells and that induces IFN-␥ production (51,52,54). IL-12 also inhibits Th2 class switching by repression of the IL-4 cytokine (15,17,46,54,55). Moreover, treatment with recombinant IL-12 has been shown to have positive effects on bronchial hyperresponsiveness and the eosinophilic response (11). Unfortunately, despite the therapeutic potential of this molecule, the toxicity of systemic IL-12 treatment observed during clinical trials has limited its use (18,31,32,33,40). This toxicity correlates with increased IFN-␥ levels, decreased glucose levels, and altered histological responses in the spleen and duodenum. This has motivated several recent investigations demonstrating that intranasal delivery of IL-12 is a less toxic route of inoculation compared to the commonly used systemic one (6,7,26).The gram-positive and nonpathogenic...

Allergy Therapy by Intranasal Administration with Recombinant <i>Lactococcus lactis</i> Producing Bovine β-Lactoglobulin

“…Altogether, these data suggest that LL and LL-BLG treatments have a moderate but significant effect on the elicitation of the allergic reaction. On the other hand, while prophylactic intranasal administration of BLG induced BLG tolerance, intranasal BLG treatment after sensitization further enhances the elicitation of the allergic reaction in the respiratory tract, as hypothesized in our previous study [20]. This further demonstrates the interest of administration of BLG entrapped in recombinant bacteria for our purpose.…”

“…We have previously engineered a L. lactis strain producing BLG (strain hereafter called LL-BLG) and demonstrated that intranasal administration of LL-BLG results in the induction of a BLG-specific immune response in mice [17, 18] and partial protection for further sensitization [19, 20]. The aim of the present study was to evaluate the immunomodulatory effects of LL-BLG strain in a therapeutic protocol, both on ongoing allergen sensitization induced by intragastric administration of cows’ milk with cholera toxin, and on the elicitation of the allergic reaction after challenge with BLG.…”

Food allergy

“…Strategies targeting cytokines (108) or TLR-9 (109) have been investigated to promote Th1-type immune responses as a potential therapeutic approach, and applications in the field of food allergies are emerging.…”

Strategies of mucosal immunotherapy for allergic diseases

“…109 Coadministration of live lactococci producing IL-12 and BLG/i.n. 110 Abbreviations: BLG, bovine b-lactoglobulin; CS, chitosan; CIN, chitosan/IFN-c pDNA nanoparticle; CTB, cholera toxin B; HDM, house dust mite; Der p, Dermatophagoides pteronyssinus; i.h., inhalation; i.n., intranasal; i.t., intratracheal; ODN, oligodeoxynucleotide; OVA, ovalbumin.…”

“…Similarly, intranasal co-administration of live lactococci producing IL-12 and bovine b-lactoglobulin, a major cows' milk allergen, could also improve the efficiency of tolerance induction by intranasal administration of bovine b-lactoglobulin. 110 Interestingly, IL-10-inducing adjuvants such as 1alpha, 25-dihydoxyvitamin D3 plus dexamethasone and L. plantarum 111 can both significantly enhance sublingual immunotherapy (SLIT) efficacy in a murine asthma model.…”