Helminth-induced immunoregulation of an allergic response to food.

Work from our laboratory has shown that an enteric helminth infection can act as an adjuvant to prime for a Th2-biased response to a typically tolerogenic form of dietary antigen. Helminth infection did not, however, prime for an allergic response. Using a model in which systemic anaphylactic symptoms and antigen specific IgE are induced in C3H/HeJ mice by repeated intragastric administration of peanut antigen with the mucosal adjuvant cholera toxin we showed that an enteric helminth infection protects against the development of food allergy. Helminth-dependent protection against allergy was abrogated when the helminth-infected, allergen-sensitized mice were treated with neutralizing antibodies to IL-10. Recent work from our laboratory and others has implicated helminth induced immunoregulatory cells in protection against allergy. We will discuss the characteristics of the immunoregulatory cell populations that have been described and the mechanism(s) by which they may function in the suppression of allergy.

Mucosal immunity and allergic responses: lack of regulation and/or lack of microbial stimulation?

Allergic hyperreactivity is defined as an exaggerated immune response [typically immunoglobulin E (IgE) but also non-IgE mediated] toward harmless antigenic stimuli. The prevalence of allergic disease has increased dramatically during the last 20 years, especially in developed countries. Both genetic and environmental factors contribute to susceptibility to allergy. Evidence has emerged supporting the hypothesis that a reduction in antigenic stimulation brought about by widespread vaccination, improvements in standards of hygiene, and extensive use of antibiotics has contributed to the dysregulation of T-helper 2 cell (Th2) type responsiveness that typifies allergy. Regulation of the inherently Th2-biased mucosal immune response is crucial both to the maintenance of homeostasis at this strategic defensive barrier and to the prevention of allergic disease. The ability of Th1 responses to counter-regulate Th2 reactivity is well characterized. More recently, interest has centered on regulatory T cells, which can suppress both Th1 and Th2 cells through the secretion of immunosuppressive cytokines such as interleukin-10 and transforming growth factor-beta. In this review, we discuss the basic cellular mechanisms of allergic diseases at mucosal surfaces, focusing on allergic responses to food, before examining newer work that suggests the induction of allergic hyperreactivity is due to a deficient immunoregulatory network, a lack of microbial stimulation, or both.

Preventing intolerance: the induction of nonresponsiveness to dietary and microbial antigens in the intestinal mucosa.

The gut-associated lymphoid tissue (GALT) is constantly exposed to a variety of Ags and must therefore decipher a large number of distinct signals at all times. Responding correctly to each set of signals is crucial. When the GALT receives signals from the intestinal flora or food Ags, it must induce a state of nonresponsiveness (mucosal tolerance). In contrast, when pathogenic bacteria invade the intestinal mucosa, it is necessary to elicit strong T and B cell responses. The GALT is therefore in the position of constantly fighting intolerance to food and the commensal flora while effectively battling infectious microbes. Determining precisely which type of response to generate in each case is key to the prevention of immune dysregulation and tissue damage.

Toll-like receptor 4 signaling by intestinal microbes influences susceptibility to food allergy.

The mechanisms by which signaling by the innate immune system controls susceptibility to allergy are poorly understood. In this report, we show that intragastric administration of a food allergen with a mucosal adjuvant induces allergen-specific IgE, elevated plasma histamine levels, and anaphylactic symptoms in three different strains of mice lacking a functional receptor for bacterial LPS (Toll-like receptor 4 (TLR4)), but not in MHC-matched or congenic controls. Susceptibility to allergy correlates with a Th2-biased cytokine response in both the mucosal (mesenteric lymph node and Peyer's patch) and systemic (spleen) tissues of TLR4-mutant or -deficient mice. TLR4-mutant mice are not inherently impaired in their ability to regulate Th1 cytokine production because they respond to stimulation via TLR9. Coadministration of CpG oligodeoxynucleotides during sensitization of TLR4-mutant mice with allergen plus CT abrogates anaphylactic symptoms and Ag-specific IgE, and results in a Th1-polarized cytokine response. When the composition of the bacterial flora is reduced and altered by antibiotic administration (beginning at 2 wk of age), TLR4 wild-type mice become as susceptible to the induction of allergy as their TLR4-mutant counterparts. Both allergen-specific IgE and Th2 cytokine responses are reduced in antibiotic-treated mice in which the flora has been allowed to repopulate. Taken together, our results suggest that TLR4-dependent signals provided by the intestinal commensal flora inhibit the development of allergic responses to food Ags.

An enteric helminth infection protects against an allergic response to dietary antigen.

Although helminths induce a polarized Th2 response they have been shown, in clinical studies, to confer protection against allergies. To elucidate the basis for this paradox, we have examined the influence of an enteric helminth infection on a model of food allergy. Upon Ag challenge, mice fed peanut (PN) extract plus the mucosal adjuvant cholera toxin (CT) produced PN-specific IgE that correlated with systemic anaphylactic symptoms and elevated plasma histamine. PN-specific IgE was not induced in helminth-infected mice fed PN without CT. Moreover, when PN plus CT was fed to helminth-infected mice, both PN-specific IgE and anaphylactic symptoms were greatly diminished. The down-regulation of PN-specific IgE was associated with a marked reduction in the secretion of IL-13 by PN-specific T cells. When helminth-infected PN plus CT-sensitized mice were treated with neutralizing Abs to IL-10, the PN-specific IgE response and anaphylactic symptoms were similar to, or greater than, those seen in mice that receive PN and CT alone. Taken together, these results suggest that helminth-dependent protection against allergic disease involves immunoregulatory mechanisms that block production of allergen-specific IgE.