Intestinal Helminths Protect in a Murine Model of Asthma

Abstract

Underdeveloped nations are relatively protected from the worldwide asthma epidemic; the hygiene hypothesis suggests this is due to suppression of Th2-mediated inflammation by increased exposure to pathogens and their products. Although microbial exposures can promote Th2-suppressing Th1 responses, even Th2-skewing infections, such as helminths, appear to suppress atopy, suggesting an alternate explanation for these observations. To investigate whether induction of regulatory responses by helminths may counter allergic inflammation, we examined the effects of helminth infection in a murine model of atopic asthma. We chose Heligosomoides polygyrus, a gastrointestinal nematode, as the experimental helminth; this worm does not enter the lung in its life cycle. We found that H. polygyrus infection suppressed allergen-induced airway eosinophilia, bronchial hyperreactivity, and in vitro allergen-recall Th2 responses in an IL-10-dependent manner; total and OVA-specific IgE, however, were increased by worm infection. Finally, helminth-infected mice were protected against eosinophilic inflammation induced by adoptive transfer of OVA-stimulated CD4+ cells, and transfer of cells from helminth-infected/OVA-exposed mice suppressed OVA-induced eosinophilic inflammation, suggesting a role for regulatory cells. Increased CD4+CD25+Foxp3+ cells were found in thoracic lymph nodes of helminth-infected/OVA-exposed mice. Helminthic colonization appears to protect against asthma and atopic disorders; the regulatory cytokine, IL-10, may be a critical player.

A Helminth Immunomodulator Reduces Allergic and Inflammatory Responses by Induction of IL-10-Producing Macrophages

“…The importance of IL-10 in cystatin-induced protection against asthma is in accordance with reports that IL-10 modulates allergic immune responses in mice infected with the gut nematode Heligmosomoides polygyrus or the blood fluke Schistosoma mansoni (39,40). However, other studies demonstrate that helminth-induced protection against allergic disease is not dependent on IL-10 and they propose a role for TGF-␤ (6, 41).…”

Resistance to experimental autoimmune encephalomyelitis development in Lewis rats from a conventional animal facility

“…This possibility is based on a growing body of evidence suggesting that excessive hygiene conditions could contribute to the increased incidence of allergic and autoimmune diseases in developed countries. This idea has been named "hygiene hypothesis" and has been supported by investigations in epidemiology (Cooke et al 2004), basic immunology (Vercelli 2006), animal models (Kitagaki et al 2006), and human trials with probiotic agents (Floch & Monrrose 2005). A prominent theme emerging from this research has been the discovery of a relative deficiency of T-regulatory cell activity in allergy and autoimmunity (Randolph & Fathman 2006).…”

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

“…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].…”

“…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]. …”