Genetic Selection for Susceptibility to Oral Tolerance Leads to a Profound Reduction of the Acute Inflammatory Response

Silva, Maria de Fátima Sarro da; Nóbrega, Alberto; Barja-Fidalgo, Tereza Cristina; Brando-Lima, Aline C.; Cunha, Fernando; Silva, Antonio Carlos da

doi:10.1196/annals.1309.024

Cited by 6 publications

(8 citation statements)

References 6 publications

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“…Moreover, TR mice survival at the late phases after infection may be explained by their intense inflammatory response controlling the proliferation of the parasite during the initial stages of infection, allowing the mice to have a milder illness and survive to late periods of infection. This is corroborated by the fact that TR mice possess few CD4 + Foxp3 + cells, producing low anti-inflammatory cytokines levels which imply a high inflammatory potential [26] , [28] . TS mice, on the other hand, carry high numbers of regulatory T cells CD4 + Foxp3 + , thus, better regulating the inflammatory response [26] , [28] .…”

Section: Discussionmentioning

confidence: 79%

“…From the genetic point of view, the oral tolerance character is under polygenic control, and the resistant (TR mice) and susceptible (TS mice) lines are genetically homogeneous at the relevant loci for the selected character and heterogeneous in terms of background genes [24] . As far as the immunological perspective is concerned, TR mice are characterized by the development of strong Th1 and Th2 immune responses and higher acute inflammatory and allergic responses with low CD4+Foxp3+ Treg cell frequency producing insufficient IL-10 levels, in contrast to TS mice [26] , [27] , [28] . In previous studies, the TR and TS mice proved to be good models when infected with intracellular parasites.…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

et al. 2014

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Toxoplasmosis is a worldwide disease with most of the infections originating through the oral route and generates various pathological manifestations, ranging from meningoencephalitis to retinochoroiditis and inflammatory bowel disease. Animal models for these pathologies are scarce and have limitations. We evaluated the outcome of Toxoplasma gondii oral infection with 50 or 100 cysts of the ME-49 strain in two lines of mice with extreme phenotypes of susceptibility (TS) or resistance (TR) to immune oral tolerance. Therefore, the aim of this study was to evaluate the behaviour of TS and TR mice, orally infected by T. gondii, and determine its value as a model for inflammatory diseases study. Mortality during the acute stage of the infection for TR was 50% for both dosages, while 10 and 40% of the TS died after infection with these respective dosages. In the chronic stage, the remaining TS succumbed while TR survived for 90 days. The TS displayed higher parasite load with lower intestinal inflammation and cellular proliferation, notwithstanding myocarditis, pneumonitis and meningoencephalitis. TR presented massive necrosis of villi and crypt, comparable to inflammatory bowel disease, with infiltration of lymphoid cells in the lamina propria of the intestines. Also, TR mice infected with 100 cysts presented intense cellular infiltrate within the photoreceptor layer of the eyes, changes in disposition and morphology of the retina cell layers and retinochoroiditis. During the infection, high levels of IL-6 were detected in the serum of TS mice and TR mice presented high amounts of IFN-γ and TNF-α. Both mice lineages developed different disease outcomes, but it is emphasized that TR and TS mice presented acute and chronic stages of the infection, demonstrating that the two lineages offer an attractive model for studying toxoplasmosis.

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Section: Discussionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

et al. 2014

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“…5a-c). Recent results show that the TS mice are lowinflammatory mice while TR and the F 1 mice are fivefold more inflammatory than TS mice 39 . This is suggestive of an association between OT and inflammation.…”

Section: Discussionmentioning

confidence: 99%

“…Treg cells are indispensable for homeostasis and regulation of the immune system, and there is also a suggestion that multiple signals could confer resistance to Treg cell suppression. 40 TR mice produce higher prostaglandin E2, intercellular adhesion moelcule, IL-1 and IL-12 levels and acute inflammatory responses 39 , probably as a consequence of low IL-10 levels, and these molecules can signal resistance to suppression.…”

Section: Discussionmentioning

confidence: 99%

“…37 The information that IL-4 and IL-10 inhibit the Th1 responses, and that IL-4, IL-10 and IFN-c are required to control the Th17 responses, 38 suggest the participation of these cytokines in establishing phenotypes of specific OT susceptibility/resistance and in the diverse inflammatory responses of TR and TS mice. 39 Regulatory T lymphocytes (Treg cells) are important regulators of the immune response that contribute to the maintenance of intestinal immune homeostasis by actively suppressing reactive responses to food antigens and commensal flora. Naive TS mice have higher CD25 + and Foxp3 + mean frequencies among CD4 + lymphocytes than TR mice (Fig.…”

Section: Discussionmentioning

confidence: 99%

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Innate profiles of cytokines implicated on oral tolerance correlate with low‐ or high‐suppression of humoral response

et al. 2010

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Summary Oral tolerance (OT) is being studied with great interest because of its therapeutic potential in allergy and autoimmunity. In the present study, two mouse strains with extreme phenotypes of OT susceptibility (TS) or resistance (TR) to ovalbumin (OVA) were used to demonstrate whether the tr and ts genes, cumulated during 18 generations of bi‐directional genetic selection, influence expression of immunobiological traits in naive or antigen‐gavaged TR/TS mice. The difference in anti‐OVA titres was 2048‐fold between OVA‐gavaged TS and TR mice. Tolerance susceptibility to OVA gavage in individuals from a (TS × TR)F2 population was 24% high‐susceptibility, 62% low‐susceptibility and 14% non‐tolerant. Different antigens, unrelated to OVA, were tested by gavage and TS mice were generally susceptible while TR mice were resistant. The stability of TS and TR phenotypes was not affected by the use of strict protocols of intraperitoneal immunization or feeding over 30 consecutive days. The levels of interleukin‐2 (IL‐2), IL‐4, interferon‐γ and IL‐10 cytokines evaluated in concanavalin A‐stimulated spleen cells from naive mice and in OVA‐stimulated spleen cells from OVA‐gavaged mice were higher in TS mice. Interleukin‐10 was up‐regulated in OVA‐gavaged TS mice and down‐regulated in TR mice. In naive mice, the percentage of CD4+ CD25+ and CD4+ Foxp3+ spleen cells and IL‐10 expression by CD4+ cells was significantly higher in TS mice. These results indicate that regulation of IL‐10 expression could be an important factor contributing to the mechanisms controlling OT susceptibility, and that the OT responses of TR and TS individuals strongly correlate with their innate potential to secrete this cytokine.

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Morphological tegument alterations of adult Schistosoma mansoni, harbored in non anti-helminthic treated, high-immune-tolerogenic and low-inflammatory mice

et al. 2010

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The present study exhibits original results of S. mansoni tegumental alterations due to contact with the immune system of non anti-helminthic treated mice. We compared, by SEM, the tegument of adult worms recovered from strains of mice genetically selected to extreme phenotypes of resistance (TR strain) and susceptibility (TS strain) to egg-albumin oral tolerance (OT). The parasites recovered from TR mice displayed no morphologic alteration, while specimens collected from TS mice presented tubercle swelling with blunted and shortened spines in lower density, increased sensory organelle numbers, fusion and tegumental ridge peeling. These tegument alterations were similar to those described for Artemether or Praziquantel treatment, supporting observations that the host immune system influences the development and function of the tegument of worms harbored in both anti-helminthic treated and non-treated mice. Our results are indicative that the development and function of the worm tegument depend on the immune regulatory capacity of each individual host.

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Genetic Selection for Susceptibility to Oral Tolerance Leads to a Profound Reduction of the Acute Inflammatory Response

Cited by 6 publications

References 6 publications

Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

Toxoplasma gondii Oral Infection Induces Intestinal Inflammation and Retinochoroiditis in Mice Genetically Selected for Immune Oral Tolerance Resistance

Innate profiles of cytokines implicated on oral tolerance correlate with low‐ or high‐suppression of humoral response

Morphological tegument alterations of adult Schistosoma mansoni, harbored in non anti-helminthic treated, high-immune-tolerogenic and low-inflammatory mice

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