Neutralizing Anti-IL-10 Antibody Blocks the Protective Effect of Tapeworm Infection in a Murine Model of Chemically Induced Colitis

Hunter, Malcolm; Wang, Arthur; Hirota, Christina L.; McKay, Derek M.

doi:10.4049/jimmunol.174.11.7368

Cited by 151 publications

(227 citation statements)

References 48 publications

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“…Thus, in the presence of the physiological regulatory circuits, reduced IL-10 allows p110d-deficient T cells to develop a predominant, unopposed type 1 response. This interpretation is consistent with the previously described sporadic inflammatory bowel disease (IBD) phenotype occurring in older p110d-inactivated mice [11], since IBD is known to involve deregulated Th1 responses and is opposed by IL-10 [25].…”

Section: Discussionsupporting

confidence: 92%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

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Phosphoinositide 3-kinases (PI3K) regulate immune activation via their roles in signal transduction of multiple classes of receptors. Here, we examined the effect of genetic inactivation of the hemopoietic cell-restricted PI3K isoform p110d on systemic cytokine and chemokine responses and allergic airway inflammation. We found that type 2 cytokine responses (IL-4, IL-5 and IL-13) are significantly decreased in p110d mutants, whereas type 1 cytokine responses (IFN-c and CXCL10) were robust. Elevated IFN-c production during the primary response to ovalbumin (OVA) was associated with reduced production of the regulatory cytokine IL-10. IFN-c and IL-10 production normalized after secondary OVA immunization; however, type 2 cytokine production was persistently reduced. Type 2 cytokine-dependent airway inflammation elicited by intranasal challenge with OVA was dramatically reduced, with reduced levels of eosinophil recruitment and mucus production observed in the lungs. Induction of respiratory hyper-responsiveness to inhaled methacholine, a hallmark of asthma, was markedly attenuated in p110d-inactivated mice. Adoptive transfer of OVA-primed splenocytes from normal but not p110d-inactivated mice could induce airway eosinophilia in naive, airway-challenged recipient mice. These data demonstrate a novel functional role for p110d signaling in induction of type 2 responses in vivo and may offer a new therapeutic target for Th2-mediated airway disease. IntroductionPhosphoinositide 3-kinases (PI3K) are key signaling enzymes regulating immune function [1,2]. PI3K are activated by stimulation through a variety of receptor types, including antigen receptors, costimulatory receptors and certain cytokine receptors. PI3K function by phosphorylating specific plasma membrane phospholipids to generate short-lived, membrane-integral lipid [3,4]. Effects of regulatory subunit deficiencies on T cells are less clear: deficiency of the p85a regulatory subunit for class 1A PI3K was reported to have no effect on T cell activation in vitro, while deficiency in the p85b regulatory subunit increased T cell proliferation in vitro [5]. One group found that p85-deficient mice have enhanced responses to Leishmania infection [6], but reduced immunity to nematode infection [7], suggesting that impaired class IA PI3K signaling leads to an immune dysregulation rather than a general immunodeficiency. However, the interpretation of these studies is complicated because regulatory subunits each affect the stability and activity of multiple catalytic subunits and may have adaptor functions in signaling independent of PI3K catalytic subunits.Recent work has begun to explore the specific roles of different PI3K catalytic subunit isoforms in immune function. Analysis of p110a and p110b deficiency has been hindered by the lethality of these mutations [8,9]. Mice deficient in the class IB subunit p110c are viable and have defects in T cell development and activation, as well as severe defects in neutrophil function, while B cell activation appears normal [1...

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Section: Discussionsupporting

confidence: 92%

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

et al. 2007

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“…Fur was removed from the knees of anesthetized mice using hair removal lotion (Nair; Church & Dwight Canada), and CFA (Sigma) was injected into the articular joint space via a 30G1/2-gauge needle, as previously described (14,15 (9). Additional mice were gavaged with 10 H diminuta cysticercoids that had been destroyed by sonication and boiled for 10 minutes.…”

Section: Methodsmentioning

confidence: 99%

Infection with an intestinal helminth parasite reduces Freund's complete adjuvant–induced monoarthritis in mice

Shi¹,

Wang²,

Prescott³

et al. 2011

Arthritis & Rheumatism

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Objective. Assessment of infection with helminth parasites in murine models of disease could identify antiinflammatory mechanisms that translate into treatments for arthritic disease. The aim of this study was to test the ability of infection with the tapeworm Hymenolepis diminuta to ameliorate Freund's complete adjuvant (CFA)-induced monoarthritis in mice.Methods. Mice received CFA with or without H diminuta, and knee swelling, pain, and measures of inflammation were assessed.Results. Injection of CFA resulted in rapid (within 24 hours) and sustained (lasting 20 days) knee swelling, a decreased pain threshold, increased blood flow to the knee, and increased production of tumor necrosis factor ␣ and interleukin-12p40 (IL-12p40). In mice that were infected with H diminuta 8 days prior to receiving CFA, the severity of arthritis was reduced as assessed by these indices of inflammation and infection 2 days after CFA injection and resulted in more rapid resolution of knee swelling. This antiarthritic effect required a viable infection and was dependent on adaptive immunity, because infection with H diminuta did not protect mice lacking T cells and B cells or the IL-4 receptor ␣ chain from CFA-induced inflammation. Interleukin-10 was of prime importance in the antiarthritic effect, because IL-10-knockout mice were not protected by infection, the antiarthritic effect was ablated by use of neutralizing IL-10 antibodies, and transfer of CD4؉ cells from infected wild-type mice but not IL-10-knockout mice significantly reduced CFAinduced knee swelling.Conclusion. In mice, the adaptive immune response to infection with H diminuta involves mobilization of IL-10, which has the concomitant advantage of dampening the innate immune responses that drive CFA-induced joint inflammation.

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“…1 Collectively, these studies have shown that as a consequence of the host response to infection with helminth parasites, there is mobilization of transforming growth factor (TGF)-␤, interleukin (IL)-10, Foxp3 ϩ regulatory T cells, alternatively activated macrophages, and inhibition of IL-17-and interferon (IFN)-␥-driven events: one, or a combination, of these events could block the development of autoimmune and inflammatory disorders. [2][3][4][5][6][7] These findings have been complemented by intriguing data suggesting that infection with viable parasitic nematodes could be a treatment for patients with inflammatory bowel disease (IBD) 8 or asthma, 9 whose condition is not managed by conventional therapies.…”

mentioning

confidence: 87%

“…delivery in accordance with our earlier study and for comparisons with the DNBS model of colitis. 3 Experiments conformed to the Canadian guidelines for animal welfare.…”

Section: Mice and Induction Of Colitismentioning

confidence: 99%

“…11 This coupled to the spectre of iatrogenic disease 12 means that one must be vigilant of the potential for infection with helminth parasites to exaggerate disease, and to provoke deleterious sideeffects. In this context, we showed that in contrast to the dinitrobenzene sulfonic acid (DNBS) model of colitis, 3 mice infected with the rat tapeworm Hymenolepis diminuta developed significantly more severe colonic inflammation when challenged intrarectally (ir.) with oxazolone.…”

mentioning

confidence: 99%

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Exacerbation of Oxazolone Colitis by Infection with the Helminth Hymenolepis diminuta

Wang

Fernando²,

Leung³

et al. 2010

The American Journal of Pathology

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Neutralizing Anti-IL-10 Antibody Blocks the Protective Effect of Tapeworm Infection in a Murine Model of Chemically Induced Colitis

Cited by 151 publications

References 48 publications

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Role of the phosphoinositide 3‐kinase p110δ in generation of type 2 cytokine responses and allergic airway inflammation

Infection with an intestinal helminth parasite reduces Freund's complete adjuvant–induced monoarthritis in mice

Exacerbation of Oxazolone Colitis by Infection with the Helminth Hymenolepis diminuta

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