Suppression of type 2 immunity and allergic airway inflammation by secreted products of the helminthHeligmosomoides polygyrus

Abstract

Allergic asthma is less prevalent in countries with parasitic helminth infections, and mice infected with parasites such as Heligmosomoides polygyrus are protected from allergic airway inflammation. To establish whether suppression of allergy could be mediated by soluble products of this helminth, we tested H. polygyrus excretory-secretory (HES) material for its ability to impair allergic inflammation. When HES was added to sensitising doses of ovalbumin, the subsequent allergic airway response was suppressed, with ablated cell infiltration, a lower ratio of effector (CD4 + CD25 + Foxp3 − ) to regulatory (CD4 + Foxp3 + ) T (Treg) cells, and reduced Th1, Th2 and Th17 cytokine production. HES exposure reduced IL-5 responses and eosinophilia, abolished IgE production and inhibited the type 2 innate molecules arginase-1 and RELM-α (resistin-like molecule-α). Although HES contains a TGF-β-like activity, similar effects in modulating allergy were not observed when administering mammalian TGF-β alone. HES also protected previously sensitised mice, suppressing recruitment of eosinophils to the airways when given at challenge, but no change in Th or Treg cell populations was apparent. Because heat-treatment of HES did not impair suppression at sensitisation, but compromised its ability to suppress at challenge, we propose that HES contains distinct heat-stable and heat-labile immunomodulatory molecules, which modulate pro-allergic adaptive and innate cell populations.Keywords: Allergy r Eosinophils r IgE r Infection r Macrophages IntroductionAllergic asthma has dramatically increased in prevalence in developing countries, exceeding 5% of the Western European and North American populations [1]. This contrasts with much lower asthma incidence in tropical countries that have significant levels of parasite infections, and these observations have stimulated research into the effects of parasitic organisms on human allergy [2][3][4]. From these studies, it has emerged that allergic diseases are least common in parts of the world with high helminth endemicity, and that within endemic populations the prevalence of atopy is significantly lower in individuals with chronic worm infections [5][6][7][8][9][10].Correspondence: Dr. Rick M. Maizels e-mail: rick.maizels@ed.ac.ukWhile a causal link between human helminth infections and reduced allergy has yet to be proven [2], chemotherapeutic clearance of intestinal helminths can result in accentuated atopic responsiveness [11][12][13] and helminth infection blocks overt allergy in a number of animal models [14][15][16][17]. The degree to which helminths may influence allergy, however, is clearly variable between different parasite species [18], and is probably dependent upon the duration and intensity of infection [2,19], each factors that need to be taken into account in assessing this interaction.The concept that helminths may act in a beneficial way for therapy of immunological disorders is one that has been gaining * These author contributed equally to this work. Eur. J. Immunol. 20...

Helminth Infections and Host Immune Regulation

“…The transfer of Tregs induced in vitro by HES, or by mammalian TGF-␤, also abrogated airway allergic inflammation, confirming the ability of helminth-induced Tregs to suppress allergic pathology (100). When administered with an allergen in vivo, HES can also abolish the subsequent allergic response to airway challenge (193).…”

Immunity to gastrointestinal nematode infections

“…220 However, other potential long-lasting consequences of acute T. muris infection remain unexplored. In contrast, H. polygyrus appears to be protective in several inflammatory models, 221,222 and this has been attributed to its ability to dampen inflammation by promoting the generation and function of regulatory T cells via some of its secreted proteins. 223,224 Hence, the hygiene hypothesis might apply only to a narrow group of nematodes and it is important that we distinguish between general phenomena of parasite infection (such as the importance of IL-13) and more specific ones (such as the contribution of eosinophils) if we are to apply our knowledge to patients in the clinic.…”

Cultivation of <em>Heligmosomoides Polygyrus:</em> An Immunomodulatory Nematode Parasite and its Secreted Products

“…and c) blockade of IL-33 production 20 . HES has been shown to be protective when administered at sensitization or challenge in the OVA-alum model of asthma 19 and also when administered intranasally with Alternaria extract allergen 20 …”

“…There has consequently been great interest in the potential of Excretory-Secretory molecules from this parasite ("HES") to down-modulate pathology in vivo 17,18 . Indeed, protective effects are seen following treatment of mice with HES products 19 through pathways which are now being identified 18,20 . Here we describe a protocol for the reliable production of Heligmosomoides polygyrus and recovery of its secreted products that can be further utilized for a range of functional biochemical and immunological investigations.…”