Helminth Antigens Enable CpG-Activated Dendritic Cells to Inhibit the Symptoms of Collagen-induced Arthritis through Foxp3+ Regulatory T Cells

Carranza, Franco; Falcón, Cristián; Núñez, Nicolás Gonzalo; Knubel, Carolina Paola; Correa, Silvia G.; Bianco, Ismael D.; Maccioni, Mariana; Fretes, Ricardo; Triquell, María Fernanda; Motrán, Claudia Cristina; Cervi, Laura

doi:10.1371/journal.pone.0040356

Cited by 52 publications

(52 citation statements)

References 43 publications

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“…Indeed, protection induced by infection with the live parasite was found to be TGF-b dependent. It has also been reported that somatic extracts from F. hepatica enhance Treg differentiation (20). In this study, we found that FHES induced dose-dependent production of TGF-b by GM-CSF-expanded BMDCs ( Fig.…”

Section: Role Of Regulatory Cytokines and Cells In The Immunosuppresssupporting

confidence: 75%

“…The live fluke probably exerts distinct immunomodulatory effects to FHES, because of the additional effect of tegumental and somatic Ags. Total extract of F. hepatica, a soluble preparation of homogenized adult flukes that contains tegumental and somatic Ags, was shown to protect mice from collagen-induced arthritis in a TGF-b and Treg-dependent manner (20). In contrast, the current study demonstrates that ES fraction suppresses not by Tregs but by modulation of innate immune responses, specifically the induction of IL-5 and IL-33.…”

Section: Discussioncontrasting

confidence: 55%

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Helminth Products Protect against Autoimmunity via Innate Type 2 Cytokines IL-5 and IL-33, Which Promote Eosinophilia

Finlay

Stefańska

Walsh

et al. 2016

The Journal of Immunology

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Epidemiologic studies in humans have demonstrated that infection with helminth parasites is associated with a reduced risk of developing autoimmune diseases. Mechanistic studies in mice have linked the protective effect of helminths on autoimmunity to the suppressive activity of helminth-induced regulatory T cells (Tregs) or Th2 cells. In this study, we demonstrate that treatment of mice with Fasciola hepatica excretory-secretory products (FHES) attenuated the clinical signs of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Protection was associated with a significant reduction in the infiltration of pathogenic Th1 and Th17 cells into the brain. Although FHES enhanced anti-inflammatory cytokine and Th2 responses, protection against EAE was independent of IL-4, IL-10, and Tregs. However, administration of FHES induced production of the type 2 cytokines IL-33 and IL-5, which promoted accumulation of eosinophils. FHES-induced expansion of eosinophils and protection against EAE was lost in IL-33−/− mice and upon neutralization of IL-5. Furthermore, transfer of FHES-induced or IL-33–induced eosinophils conferred protection against EAE. In addition, treatment of mice with recombinant IL-33 attenuated autoimmunity, and this was dependent on IL-5. To our knowledge, this study is the first to report a role for helminth-induced IL-5 and IL-33 in protection against autoimmunity.

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Section: Role Of Regulatory Cytokines and Cells In The Immunosuppresssupporting

confidence: 75%

Section: Discussioncontrasting

confidence: 55%

Helminth Products Protect against Autoimmunity via Innate Type 2 Cytokines IL-5 and IL-33, Which Promote Eosinophilia

Finlay

Stefańska

Walsh

et al. 2016

The Journal of Immunology

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“…Tregs induce protection against CIA by diminishing joint inflammation (Carranza et al, 2012). Therefore, we evaluated the levels of Tregs in LNs isolated from CIA mice at day 40 and found that IQ-1S (20 and 30 mg/kg) treatment dose-dependently increased the number of CD4 1 cells expressing CD25 and Foxp3 (Fig.…”

Section: Inhibition Of Collagen-induced Arthritis By Iq-1smentioning

confidence: 94%

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Schepetkin

Kirpotina

Hammaker

et al. 2015

J Pharmacol Exp Ther

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c-Jun N-terminal kinases (JNKs) participate in many physiologic and pathologic processes, including inflammatory diseases. We recently synthesized the sodium salt of IQ-1S (11H-indeno[1,2-b]quinoxalin-11-one oxime) and demonstrated that it is a high-affinity JNK inhibitor and inhibits murine delayed-type hypersensitivity. Here we show that IQ-1S is highly specific for JNK and that its neutral form is the most abundant species at physiologic pH. Molecular docking of the IQ-1S syn isomer into the JNK1 binding site gave the best pose, which corresponded to the position of cocrystallized JNK inhibitor SP600125 (1,9-pyrazoloanthrone). Evaluation of the therapeutic potential of IQ-1S showed that it inhibited matrix metalloproteinase 1 and 3 gene expression induced by interleukin-1b in human fibroblast-like synoviocytes and significantly attenuated development of murine collagen-induced arthritis (CIA). Treatment with IQ-1S either before or after induction of CIA resulted in decreased clinical scores, and joint sections from IQ-1S-treated CIA mice exhibited only mild signs of inflammation and minimal cartilage loss compared with those from control mice. Collagen II-specific antibody responses were also reduced by IQ-1S treatment. By contrast, the inactive ketone derivative 11H-indeno[1,2-b]quinoxalin-11-one had no effect on CIA clinical scores or collagen II-specific antibody titers. IQ-1S treatment also suppressed proinflammatory cytokine and chemokine levels in joints and lymph node cells. Finally, treatment with IQ-1S increased the number of Foxp3 CD251 regulatory T cells in lymph nodes. Thus, IQ-1S can reduce inflammation and cartilage loss associated with CIA and can serve as a small-molecule modulator for mechanistic studies of JNK function in rheumatoid arthritis.

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“…Adoptive transfer of bone marrow-derived DCs pulsed with Fasciola hepatica (i.e. trematode parasite) tegument antigens and the TLR9 agonist CpG-DNA resulted in reduced severity of collagen-induced arthritis in mice that was dependent on Treg cells; F. hepatica antigen only treated DCs did not suppress arthritis [16]. Also, DCs pulsed with T. spiralis antigen protected mice from experimental autoimmune encephalitis (a model of multiple sclerosis) and while this correlated with DC production of IL-10, the mechanism(s) of action by these cells was not defined [39].…”

mentioning

confidence: 99%

Adoptive transfer of helminth antigen‐pulsed dendritic cells protects against the development of experimental colitis in mice

et al. 2015

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Infection with helminth parasites and treatment with worm extracts can suppress inflammatory disease, including colitis. Postulating that dendritic cells (DCs) participated in the suppression of inflammation and seeking to move beyond the use of helminths per se, we tested the ability of Hymenolepis diminuta antigen-pulsed DCs to suppress colitis as a novel cell-based immunotherapy. Bone marrow derived DCs pulsed with H. diminuta antigen (HD-DCs), or PBS-, BSA-, or LPS-DCs as controls, were transferred into wild-type (WT), interleukin-10 (IL-10) knock-out (KO),Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionOver the last three generations there has been a substantial rise in the incidence and prevalence of inflammatory disease especially in developed nations, but also in developing countries [1]. As autoimmune, inflammatory, and idiopathic diseases (e.g. inflammatory bowel disease [IBD]) emerge as global threats, and with awareness Correspondence: Dr. Derek M. McKay e-mail: dmckay@ucalgary.ca of the shortcomings of current therapies for these chronic debilitating conditions, there is a pressing need to advance knowledge of novel means to treat and ultimately cure inflammatory disease. Amongst many potential candidates, infection with helminth parasites has generated considerable interest because the host response to these parasites involves a range of endogenous immunoregulatory events. Infection with helminth parasites is a potent stimulus on the mammalian immune system, with remarkable commonality between mice and humans [2]. Furthermore, helminths are not mere passive victims of the host immune response; they C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2015. 45: 3126-3139 Immunomodulation 3127 have evolved multiple means to circumvent the host's anti-worm response [3]. Consequently, it was postulated that infection with parasitic helminths could ameliorate concomitant disease. Preclinical murine experimentation, case reports, and small clinical trials have demonstrated that infection with helminths reduces the severity of inflammatory disease [4][5][6][7], via a variety of mechanisms such as mobilization of regulatory T (Treg) and B (Breg) cells and the synthesis of .As an alternative to infection with viable helminth parasites, systemic administration of crude extracts of a variety of helminth parasites has been shown to inhibit inflammation, including colitis [9][10][11]. However, to date, it has proven challenging to isolate pure single bioactive molecules from helminth parasites [12][13][14] that could serve as new drugs: indeed, a combination of helminthderived molecules may be required to effectively suppress immune activity and protect against immunopathology/inflammatory disease.Expanding upon the evidence that infection with helminth parasites or treatment with worm extracts inhibit inflammation, one can hypothesize that priming a specific immune regulatory or effector cell in vit...

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Helminth Antigens Enable CpG-Activated Dendritic Cells to Inhibit the Symptoms of Collagen-induced Arthritis through Foxp3+ Regulatory T Cells

Cited by 52 publications

References 43 publications

Helminth Products Protect against Autoimmunity via Innate Type 2 Cytokines IL-5 and IL-33, Which Promote Eosinophilia

Helminth Products Protect against Autoimmunity via Innate Type 2 Cytokines IL-5 and IL-33, Which Promote Eosinophilia

Anti-Inflammatory Effects and Joint Protection in Collagen-Induced Arthritis after Treatment with IQ-1S, a Selective c-Jun N-Terminal Kinase Inhibitor

Adoptive transfer of helminth antigen‐pulsed dendritic cells protects against the development of experimental colitis in mice

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