Intestinal Nematode Infection Ameliorates Experimental Colitis in Mice

W Khan

P Blennerhasset

A Varghese

S Chowdhury

P Omsted

Y Deng

S Collins

Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada

^{Corresponding author. Mailing address: Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada. Phone: (905) 521-2100, ext. 2100. Fax: (905) 521-4958. E-mail:}ac.retsamcm@snillocs.

Received 2002 Jan 29; Revised 2002 Apr 2; Accepted 2002 Jul 30.

Abstract

Epidemiological studies suggest that inflammatory bowel disease (IBD) is common in developed countries and rare in countries where intestinal nematode infections are common. T cells are critical in many immune responses, including those associated with IBD and nematode infection. Among the distinct T helper (Th) cell subsets, Th1-type immune response is predominantly associated with Crohn's disease, while many nematode infections generate a strong Th2 response. The reciprocal cross regulation between Th1 and Th2 cells suggests that generation of a Th2 response by nematodes could prevent or reduce the effects of Th1-mediated diseases. In the present study, we investigated the effect of polarizing the immune response toward the Th2 type, using intestinal nematode infection, on subsequent experimental colitis. Mice were infected with the intestinal nematode Trichinella spiralis and allowed to recover before colitis was induced with dinitrobenzene sulfonic acid. The mice were sacrificed postcolitis to assess colonic damage macroscopically, histologically, and by myeloperoxidase (MPO) activity and Th cytokines. Prior nematode infection reduced the severity of colitis both macroscopically and histologically together with a decreased mortality and was correlated with a down-regulation of MPO activity, Th1-type cytokine expression in colonic tissue, and emergence of a Th2-type immune response. These results indicate a protective role of nematode infection in Th1 cell-driven inflammation and prompt consideration of a novel therapeutic strategy in IBD based on immunological distraction.

Abstract

Inflammatory bowel disease (IBD) is a chronic relapsing inflammatory condition of the gastrointestinal tract that manifests as ulcerative colitis or Crohn's disease (3, 4, 5, 34). IBD can begin relatively early in life and persist for long periods, leading to substantial morbidity and decreased quality of life (4). The causes of IBD are unknown, but epidemiological and laboratory work suggests that environmental and genetic factors are important in the pathogenesis of the IBD which is associated with dysregulation of the mucosal immune system. IBD is most common in highly industrialized temperate regions and is rare in tropical countries with poor sanitation and overcrowding (17). The rarity of IBD in tropical countries cannot be explained on the basis of genetics alone, as descendants of immigrants from such countries acquire the higher risk of IBD of the adopted developed country (32, 40). These observations underscore the importance of environmental factors in the expression of IBD and have led to the development of the “hygiene hypothesis” of IBD, that is, that IBD occurs more commonly in societies where the prevalence of chronic enteric infestation is low (17).

Parasitic infections, particularly those due to intestinal nematodes, are most common in warm climates and in areas of overcrowding and poor sanitation. Both Crohn's disease and ulcerative colitis are rare in developing countries of Asia and Africa, where nematode infections are endemic (46, 48). The prevalence of nematode infections in the United States has been declining for the past 60 years (17), except among new immigrants from developing countries (44).

T cells constitute an important part of many immune responses, including those associated with IBD and intestinal nematode infection. T helper (Th) cell-dependent immune responses are generally divided into two major subsets, Th1 and Th2 (37). Th1 cells secrete predominantly gamma interferon (IFN-γ) and interleukin-2 (IL-2), while Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and IL-13. Th1 and Th2 cells cross regulate one another. IFN-γ secreted by Th1 cells directly suppresses IL-4 production and thus inhibits the differentiation of naïve Th cells into Th2 cells (12, 23). In contrast, IL-4 and IL-10 inhibit the secretion of IL-12 and IFN-γ, blocking polarization into Th1 cells (10, 38). The dichotomous split of Th lymphocytes into Th1 and Th2 cells has provided a convenient conceptual framework to characterize T-cell responses in different diseases.

The chronic inflammation of Crohn's disease is maintained by Th1-driven immune response. T cells isolated from the colons of patients suffering from Crohn's disease produce large amounts of IFN-γ and tumor necrosis factor alpha and little IL-4 or IL-10 (2, 5, 21). Many mouse models of experimental colitis are associated with a Th1-type immune response, reflected by infiltration of IFN-γ-producing T cells in the colon (3, 11). In these models, disease is prevented, or at least ameliorated, by treatment with IL-10, IL-4, or neutralizing antibody to IL-12 (1, 22, 28). In contrast to Crohn's disease, Th2 cells are important in host protective immunity to many helminths, including the intestinal nematode Trichinella spiralis (19, 27). Many intestinal nematodes survive for years within the intestinal tract and serve as potential sources of a Th2-type immune response. Considering the contrasting geographical distributions and immune responses of intestinal nematode infection and Crohn's disease, it has been hypothesized that environmental factors like nematode infection may have significant influence on the development of Crohn's disease (17).

To test this hypothesis, in the present study we investigated the effect on consequent experimental colitis in mice of distracting the immune response to Th2 by using nematode infection. Our results demonstrate that prior exposure of mice to T. spiralis infection effectively reduces the severity of dinitrobenzenesulfonic acid (DNBS) colitis. This is correlated with a down-regulation of myeloperoxidase (MPO) activity and IFN-γ expression and a persistence of the Th2-type immune response.

Acknowledgments

We thank A. Hirotada, E. F. Verdu, and D. McKay for valuable discussions.

This study was supported by a grant to S.M.C. from the Canadian Institutes for Health Research (CIHR).

Acknowledgments

Notes

Editor: J. M. Mansfield

Notes

Editor: J. M. Mansfield

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