Suppression of allergic airway inflammation by helminth-induced regulatory T cells

Abstract

Allergic diseases mediated by T helper type (Th) 2 cell immune responses are rising dramatically in most developed countries. Exaggerated Th2 cell reactivity could result, for example, from diminished exposure to Th1 cell–inducing microbial infections. Epidemiological studies, however, indicate that Th2 cell–stimulating helminth parasites may also counteract allergies, possibly by generating regulatory T cells which suppress both Th1 and Th2 arms of immunity. We therefore tested the ability of the Th2 cell–inducing gastrointestinal nematode Heligmosomoides polygyrus to influence experimentally induced airway allergy to ovalbumin and the house dust mite allergen Der p 1. Inflammatory cell infiltrates in the lung were suppressed in infected mice compared with uninfected controls. Suppression was reversed in mice treated with antibodies to CD25. Most notably, suppression was transferable with mesenteric lymph node cells (MLNC) from infected animals to uninfected sensitized mice, demonstrating that the effector phase was targeted. MLNC from infected animals contained elevated numbers of CD4+CD25+Foxp3+ T cells, higher TGF-β expression, and produced strong interleukin (IL)-10 responses to parasite antigen. However, MLNC from IL-10–deficient animals transferred suppression to sensitized hosts, indicating that IL-10 is not the primary modulator of the allergic response. Suppression was associated with CD4+ T cells from MLNC, with the CD4+CD25+ marker defining the most active population. These data support the contention that helminth infections elicit a regulatory T cell population able to down-regulate allergen induced lung pathology in vivo.

Structure in parasite component communities in wild rodents: predictability, stability, associations and interactions .... or pure randomness?

“…Much the same is seen when other parasites replace T. spiralis as the co-infecting species and Table 3 summarises some of the studies that have shown this to be the case. Although the mechanism of this immunodepression is not fully understood it is likely to be based on immunomodulatory factors released by the worms that specifically depress components of the host response such as mastocytosis (Behnke et al 1992 ;Wilson et al 2005 ;Rzepecka et al 2006).…”

“…Other parasites alter the balance of the host's capacity to mount Th1 and Th2 responses or affect regulatory T cells (Wilson et al 2005). By initiating a Th2-driven response in the host, helminths may make the host more susceptible to concurrent infections that are better controlled by Th1 responses and vice-versa (Graham et al 2007 ;Graham, 2008).…”

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

“…However, such effects can be beneficial by downregulating inflammatory reactions to allergens and inflammatory disorders of the intestinal tract. Studies in animal models showed that helminths can suppress airway hyperreactivity and colitis [6][7][8] and nematodes have been used to efficiently treat human inflammatory bowel disease in clinical trials [9,10]. …”

“…It has been demonstrated that nematode infections may prevent and control undesired immune reactions [6][7][8][9][10][11][12]30]. Several studies showed that the beneficial effects of the infections could be mimicked by transfer of Treg derived from nematode-infected donors to naïve recipients rendering them refractory to the inflammatory disorders such as asthma and colitis [6,8,11,12]. These data indicate that circuits of Treg action during nematode infection may also modulate unrelated bystander immune reactions and supports the view of Treg as important immunoregulators that can be modulated by parasites.…”

“…In animal models, the beneficial effects of nematode infections on inflammatory disorders were associated with the presence of Treg populations [6,11,12]. However, it is not yet clear whether such Treg suppress anti-parasite immune reactivity and thus contribute to survival and well-being of the worms, or whether they predominantly dampen immunopathology.…”