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Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome

Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome

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DEL RIO OLIVA, Marta, Christopher J. KIRK, Marcus GROETTRUP, Michael BASLER, 2022. Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome. In: European Journal of Immunology. Wiley. 52(9), pp. 1510-1522. ISSN 0014-2980. eISSN 1521-4141. Available under: doi: 10.1002/eji.202249851

@article{DelRioOliva2022-09Effec-57851, title={Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome}, year={2022}, doi={10.1002/eji.202249851}, number={9}, volume={52}, issn={0014-2980}, journal={European Journal of Immunology}, pages={1510--1522}, author={Del Rio Oliva, Marta and Kirk, Christopher J. and Groettrup, Marcus and Basler, Michael} }

<rdf:RDF xmlns:dcterms="http://purl.org/dc/terms/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:bibo="http://purl.org/ontology/bibo/" xmlns:dspace="http://digital-repositories.org/ontologies/dspace/0.1.0#" xmlns:foaf="http://xmlns.com/foaf/0.1/" xmlns:void="http://rdfs.org/ns/void#" xmlns:xsd="http://www.w3.org/2001/XMLSchema#" > <rdf:Description rdf:about="https://kops.uni-konstanz.de/rdf/resource/123456789/57851"> <dcterms:title>Effective therapy of polymyositis in mice via selective inhibition of the immunoproteasome</dcterms:title> <dcterms:issued>2022-09</dcterms:issued> <dc:creator>Del Rio Oliva, Marta</dc:creator> <dcterms:hasPart rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57851/1/delRioOliva_2-1gh11i7lxub5p4.pdf"/> <dc:creator>Kirk, Christopher J.</dc:creator> <dcterms:isPartOf rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dc:contributor>Groettrup, Marcus</dc:contributor> <dspace:isPartOfCollection rdf:resource="https://kops.uni-konstanz.de/rdf/resource/123456789/28"/> <dcterms:rights rdf:resource="http://creativecommons.org/licenses/by-nc-nd/4.0/"/> <bibo:uri rdf:resource="https://kops.uni-konstanz.de/handle/123456789/57851"/> <dc:rights>Attribution-NonCommercial-NoDerivatives 4.0 International</dc:rights> <dc:contributor>Del Rio Oliva, Marta</dc:contributor> <dc:date rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-06-28T05:48:21Z</dc:date> <dcterms:available rdf:datatype="http://www.w3.org/2001/XMLSchema#dateTime">2022-06-28T05:48:21Z</dcterms:available> <dspace:hasBitstream rdf:resource="https://kops.uni-konstanz.de/bitstream/123456789/57851/1/delRioOliva_2-1gh11i7lxub5p4.pdf"/> <dc:contributor>Kirk, Christopher J.</dc:contributor> <dcterms:abstract xml:lang="eng">Polymyositis (PM) is a chronic autoimmune inflammatory myopathy resulting in muscle weakness. The limited approved therapies and their poor efficacy contribute to its comorbidity. We investigated the therapeutic use of ONX 0914 and KZR-616, selective inhibitors of the immunoproteasome, in C protein-induced myositis (CIM), a mouse model of PM that closely resembles the human disease. Diseased mice (day 13 post-immunization) were treated with 10 mg/kg ONX 0914 or KZR-616 or vehicle on alternate days until day 28. Endpoints included muscle strength assessed by a grip strength meter, serum creatine kinase activity, histology, and immunohistochemistry analysis. Treatment with ONX 0914 or KZR-616 prevented the loss of grip strength in mice after CIM induction, while vehicle-treated animals displayed progressive muscle weakness. Immunoproteasome inhibition lowered PM-associated leukocyte infiltration of the muscle and prevented increased serum creatine kinase levels. LMP7-deficient mice were resistant to CIM induction as they depicted no alteration in the grip strength, creatine kinase (CK) levels, nor showed muscular alterations. In conclusion, selective inhibition of the immunoproteasome displays therapeutic efficacy in a pre-clinical mouse model of PM with suppression of muscle inflammation and preservation of muscle strength. Positive results from this study support the rationale for using KZR-616 in clinical studies.</dcterms:abstract> <dc:creator>Basler, Michael</dc:creator> <foaf:homepage rdf:resource="http://localhost:8080/jspui"/> <dc:creator>Groettrup, Marcus</dc:creator> <dc:language>eng</dc:language> <void:sparqlEndpoint rdf:resource="http://localhost/fuseki/dspace/sparql"/> <dc:contributor>Basler, Michael</dc:contributor> </rdf:Description> </rdf:RDF>

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