Th2–mediated host protective immunity to intestinal nematode infections

Grencis, Richard K.

doi:10.1098/rstb.1997.0123

Cited by 124 publications

(84 citation statements)

References 60 publications

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“…A majority of mouse strains are resistant to infection and expel T. muris larvae between 14 and 21 days postinfection. This expulsion has been correlated with development of a polarized Th2-type immune response (11,28). In contrast, susceptible mouse strains develop polarized Th1-type immune responses and harbor larvae that mature into adults (7,29).…”

Section: Discussionmentioning

confidence: 99%

IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection

Schopf

Hoffmann

Cheever

et al. 2002

The Journal of Immunology

195

168

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Resistance to many intestinal nematodes is dependent on the induction of polarized type 2 cytokine responses, whereas type 1 responses can exacerbate these infections. The contributions of IL-4 and IL-13 to the development of resistance have been well described for a variety of intestinal parasites; however, the role of IL-10 has not been previously investigated. In this study we infected IL-10-, IL-10/IL-4-, IL-10/IL-12-, IL-4-, and IL-12-deficient mice with Trichuris muris to determine whether IL-10 contributes to the development of immunity. Interestingly, T. muris-infected IL-10-, IL-4-, and IL-10/IL-4-deficient mice failed to expel the parasite, and animals deficient in IL-10 displayed marked morbidity and mortality. In contrast, double IL-10/IL-12-deficient mice were completely resistant and mounted a highly polarized type 2 cytokine response, demonstrating that the increased susceptibility of IL-10-deficient mice was dependent on IL-12. Further study suggested that the susceptibility of IL-10- and IL-10/IL-4-deficient mice was probably attributable to a marked increase in type 1 cytokine production in those animals. The mortality observed in T. muris-infected IL-10- and IL-10/IL-4-deficient mice correlated with increased inflammation, loss of Paneth cells, and absence of mucus in the cecum. Interestingly, survival was enhanced in T. muris-infected IL-10/IL-4-deficient mice if a broad spectrum antibiotic was administered, suggesting that an outgrowth of opportunistic bacteria was contributing to the high degree of morbidity and mortality. Overall, these studies reveal a critical role for IL-10 in the polarization of Th2 responses, development of resistance during T. muris infection, and maintenance of barrier function in the colon.

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Section: Discussionmentioning

confidence: 99%

IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection

Schopf

Hoffmann

Cheever

et al. 2002

The Journal of Immunology

195

168

View full text Add to dashboard Cite

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“…IL-13-secreting NKT cells have been implicated in the pathogenesis of both experimental asthma and ulcerative colitis models (3,8), and NK cells have been implicated in the development of allergen-induced airway inflammation in mice (9), although it is not known whether they contribute to the responses following Th2-inducing infection. Many pathological features associated with both asthma and inflammatory bowel disorders are identical with those induced by intestinal nematode infection of both the small and large bowel (3,7,10). These parasites induce in the host a strong Th2 response (10), but the etiology, in particular the role of cytokines, in intestinal tissue remodeling during these infections is poorly defined.…”

mentioning

confidence: 99%

“…Many pathological features associated with both asthma and inflammatory bowel disorders are identical with those induced by intestinal nematode infection of both the small and large bowel (3,7,10). These parasites induce in the host a strong Th2 response (10), but the etiology, in particular the role of cytokines, in intestinal tissue remodeling during these infections is poorly defined. In this study, we have sought to determine the role of IL-13 on enteric pathology during infection with the intestinal nematode, Trichinella spiralis, in a mouse model.…”

mentioning

confidence: 99%

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

McDermott

Humphreys

Forman

et al. 2005

The Journal of Immunology

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IL-13 is a Th2-derived cytokine associated with pathological changes in asthma and ulcerative colitis. Moreover, it plays a major role in the control of gut nematode infection and associated immunopathology. The current paradigm is that these effects are due to T cell-derived IL-13. We show in this study that an innate source of IL-13, the intraepithelial NK cell, is responsible for the disruption of intestinal tissue architecture and induction of goblet cell hyperplasia that characterizes infection with the intestinal helminth Trichinella spiralis. IL-13 or IL-4Rα (but not IL-4) null mice failed to induce intestinal pathology. Unexpectedly, SCID and athymic mice developed the same pathology found in immunocompetent mice following infection. Moreover, immunodeficient mice expressed IL-13 in the intestine, and abnormal mucosal pathology was reduced by in vivo administration of a soluble IL-13 antagonist. IL-13 expression was induced in non-T intraepithelial CD3− NK cells. Epithelial cells expressed the IL-13 signaling receptor, IL-13Rα1, and after infection, IL-4Rα. Furthermore, the soluble IL-13 decoy receptor IL-13Rα2, which regulates IL-13 responses, was also induced upon infection. These data provide the first evidence that intestinal tissue restructuring during helminth infection is an innate event dependent on IL-13 production by NK cells resident in the epithelium of the intestine.

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“…Trichinella spiralis infection was used for Th2 polarization (11,12). The T. spiralis parasites originated in the Department of Zoology at the University of Toronto.…”

Section: Th1 and Th2 Polarization In Vivomentioning

confidence: 99%

Lymphocyte-mediated regulation of β-endorphin in the myenteric plexus

Verma-Gandhu¹,

Verdú²,

Cohen-Lyons³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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Verma-Gandhu M, Verdu EF, Cohen-Lyons D, Collins SM. Lymphocyte-mediated regulation of ␤-endorphin in the myenteric plexus. Am J Physiol Gastrointest Liver Physiol 292: G344 -G348, 2007. First published September 7, 2006; doi:10.1152/ajpgi.00318.2006.-Lymphocytes are antinociceptive and can modulate visceral pain perception in mice. Previously, we have shown that adoptive transfer of CD4 ϩ T cells to severe combined immune-deficient (SCID) mice normalized immunodeficiency-related visceral hyperalgesia. Pain attenuation was associated with an increase in ␤-endorphin release by T cells and an upregulation of ␤-endorphin in the enteric nervous system. In this study, we investigated the relationship between T cells and opioid expression in the myenteric plexus. We examined opioid peptide and receptor expression in the myenteric plexus in the presence and absence of mucosal T cells. We found a positive association between T cells and ␤-endorphin expression; this was accompanied by a downregulation of the -opioid receptor (MOR). In vitro, T helper (Th) type 1 and type 2 cytokine stimulation of CD4 ϩ T cells or isolation of T cells from in vivo Th-polarized mice did not increase T cell release of ␤-endorphin or the induction of ␤-endorphin expression in the myenteric plexus. However, exogenous ␤-endorphin did upregulate ␤-endorphin expression, and both cycloheximide and naloxone methiodide inhibited peptide upregulation. Therefore, our results suggest that nonpolarized CD4 ϩ T cells release ␤-endorphin, which, through an interaction with MOR, stimulates an upregulation of ␤-endorphin expression in the myenteric plexus. Thus, we propose that the mechanism underlying lymphocyte modulation of visceral pain involves T cell modulation of opioid expression in the enteric nervous system. enteric nervous system; opioid; CD4 ϩ T cells MECHANISMS INVOLVED in the homeostatic regulation of visceral pain are not well understood. Visceral pain is traditionally examined in the context of inflammation; noxious inflammatory stimuli are commonly used to evaluate the effect of acute inflammation on visceral sensitivity. Several mediators released by acute inflammatory cells either directly or indirectly stimulate sensory afferent neurons in the gut and are thus are pronociceptive. Pronociceptive mediators are also released in a healthy gut; the intestine exists in a state of controlled inflammation due to continuous immune surveillance of luminal antigens (9), and the sensory apparatus is constantly exposed to inflammatory mediators, but in the absence of pain. An antinociceptive influence originating from the periphery is a plausible explanation for the absence of hyperalgesia or allodynia in a healthy gut. We consider the immune system to be a source of this antinociception. Recently, we have provided evidence for antinociception derived from mucosal T lymphocytes. We demonstrated increased visceral sensitivity in severe combined immune-deficient (SCID) mice compared with immunocompetent wildtype mice (22). Our results demonstrated a n...

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Th2–mediated host protective immunity to intestinal nematode infections

Cited by 124 publications

References 60 publications

IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection

IL-10 Is Critical for Host Resistance and Survival During Gastrointestinal Helminth Infection

Intraepithelial NK Cell-Derived IL-13 Induces Intestinal Pathology Associated with Nematode Infection

Lymphocyte-mediated regulation of β-endorphin in the myenteric plexus

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