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TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis

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dc.contributor.author Mahanty, Siddhartha
dc.contributor.author Orrego, Miguel A.
dc.contributor.author Cangalaya, Carla
dc.contributor.author Adrianzen, M. Paz
dc.contributor.author Arroyo, Gianfranco
dc.contributor.author Calcina, Juan
dc.contributor.author Gonzalez, Armando E.
dc.contributor.author García, Héctor H.
dc.contributor.author Guerra-Giraldez, Cristina
dc.contributor.author Nash, Theodore E.
dc.contributor.author Cysticercosis Working Group in Peru
dc.date.accessioned 2019-01-25T16:03:22Z
dc.date.available 2019-01-25T16:03:22Z
dc.date.issued 2017
dc.identifier.uri https://hdl.handle.net/20.500.12866/4781
dc.description.abstract BACKGROUND: Neurocysticercosis (NCC) is an infection of the brain with the larval cyst of the tapeworm, Taenia solium. Cysticidal treatment induces parasite killing resulting in a post inflammatory response and seizures, which generally requires corticosteroid treatment to control inflammation. The nature of this response and how to best control it is unclear. We investigated the anti-inflammatory effects of pretreatment with etanercept (ETN), an anti-tumor necrosis factor agent, or dexamethasone (DEX), a high potency corticosteroid, on the post treatment inflammatory response in naturally infected pigs with neurocysticercosis after a single dose of the cysticidal drug praziquantel (PZQ). METHODOLOGY/PRINCIPAL FINDINGS: We followed the methods from a previously developed treatment model of NCC in naturally infected swine. The four study groups of infected pigs included 3 groups treated with PZQ on day 0: PZQ-treated alone (100 mg/kg PO; n = 9), pretreated with dexamethasone (DEX, 0.2 mg/kg IM administered on days -1, +1 and +3; n = 6), and pretreated with etanercept (ETN, 25 mg IM per animal on days -7 and 0; n = 6). The fourth group remained untreated (n = 3). As measured by quantitative RT-PCR, ETN pretreatment depressed transcription of a wide range of proinflammatory, regulatory and matrix protease encoding genes at 120 hr post PZQ treatment in capsules of cysts that demonstrated extravasated Evans Blue (EB) (a measure of blood brain barrier dysfunction) compared to animals not receiving ETN. Transcription was significantly depressed for the proinflammatory genes tumor necrosis factor (TNF)-α, and interferon (IFN)-γ; the inflammation regulating genes cytotoxic T-lymphocyte-associated protein (CTLA)4, interleukin (IL)-13 and transforming growth factor (TGF)-β; the tissue remodeling genes matrix metalloprotease (MMP)1 and 9, tissue inhibitors of metalloproteases (TIMP)1 and 2, and the genes regulating endothelial function vascular endothelial growth factor (VEGF)1, angiopoietin (Ang)1, Ang 2, and platelet endothelial cell adhesion molecule (PECAM)-1. In contrast, transcription was only modestly decreased in the DEX pretreated pigs compared to PZQ alone, and only for TNF-α, IL-6, IFN-γ, TGF-β and Ang1. IL-10 was not affected by either ETN or DEX pretreatments. The degree of inflammation, assessed by semi-quantitative inflammatory scores, was modestly decreased in both ETN and DEX pretreated animals compared to PZQ treated pigs whereas cyst damage scores were moderately decreased only in cysts from DEX pretreated pigs. However, the proportion of cysts with EB extravasation was not significantly changed in ETN and DEX pretreated groups. CONCLUSIONS/SIGNIFICANCE: Overall, TNF-α blockade using ETN treatment modulated expression of a large variety of genes that play a role in induction and control of inflammation and structural changes. In contrast the number of inflammatory cells was only moderately decreased suggesting weaker effects on cell migration into the inflammatory capsules surrounding cysts than on release of modulatory molecules. Taken together, these data suggest that TNF-α blockade may provide a viable strategy to manage post-treatment pericystic inflammation that follows antiparasitic therapy for neurocysticercosis. en_US
dc.language.iso eng
dc.publisher Public Library of Science
dc.relation.ispartof urn:issn:1935-2735
dc.rights info:eu-repo/semantics/restrictedAccess
dc.rights.uri https://creativecommons.org/licenses/by-nc-nd/4.0/deed.es
dc.subject Animals en_US
dc.subject Anticestodal Agents/therapeutic use en_US
dc.subject Antiparasitic Agents/adverse effects/therapeutic use en_US
dc.subject Blood-Brain Barrier/drug effects en_US
dc.subject Brain/parasitology en_US
dc.subject Cytokines/genetics/immunology en_US
dc.subject Dexamethasone/administration & dosage/adverse effects en_US
dc.subject Etanercept/administration & dosage/adverse effects en_US
dc.subject Immunosuppressive Agents/administration & dosage/adverse effects en_US
dc.subject Inflammation/prevention & control en_US
dc.subject Interferon-gamma/genetics/immunology en_US
dc.subject Neurocysticercosis/complications/drug therapy/immunology/veterinary en_US
dc.subject Praziquantel/administration & dosage/adverse effects/therapeutic use en_US
dc.subject Swine en_US
dc.subject Swine Diseases/drug therapy/immunology en_US
dc.subject Taenia solium/drug effects en_US
dc.subject Tumor Necrosis Factor-alpha/antagonists & inhibitors/genetics en_US
dc.title TNF-α blockade suppresses pericystic inflammation following anthelmintic treatment in porcine neurocysticercosis en_US
dc.type info:eu-repo/semantics/article
dc.identifier.doi https://doi.org/10.1371/journal.pntd.0006059
dc.subject.ocde https://purl.org/pe-repo/ocde/ford#3.02.00 es_PE


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