| Therapeutic potential of anti-interleukin-17A aptamer: Suppression of interleukin-17A signaling and attenuation of autoimmunity in two mouse models. | |
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MedLine Citation:
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PMID: 20967861 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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OBJECTIVE: The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells, which is involved in host defense, inflammation, and autoimmune disorders. This study was undertaken to investigate the effect of a high-affinity RNA molecule, called an aptamer, against human IL-17A on IL-17A-induced signal transduction in vitro and its anti-autoimmune efficacy in vivo in 2 mouse models of inflammation. METHODS: By screening a large library of nuclease-resistant RNA oligonucleotides, we selected an RNA aptamer, Apt21-2, that binds human and mouse IL-17 and blocks the interaction between IL-17A and its receptor. The inhibition of IL-17A-mediated phosphorylation and marker protein production was analyzed in human and mouse cells. Mice with glucose-6-phosphate isomerase (GPI)-induced rheumatoid arthritis and myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis were used to assess efficacy. RESULTS: Apt21-2 prevented efficient phosphorylation of the IL-17A signaling factors IκB and JNK and inhibited the production of IL-6 in human and mouse cells. A PEGylated form of Apt21-2 (PEG21-2idT) exhibited a 50% inhibition concentration (IC(50) ) in the range of 1-2 nM and 70-80 nM in human and mouse cells, respectively. When administered immediately after immunization with GPI or MOG, PEG21-2idT inhibited in a dose-dependent manner the development of arthritic or neurologic symptoms. Significantly, PEG21-2idT slowed the progression of arthritis when administered after the onset of GPI-induced arthritis. CONCLUSION: Our findings indicate that the chemically processed anti-IL-17A aptamer PEG21-2idT inhibits the actions of IL-17A as well as the development of autoimmunity in 2 mouse models of inflammation. These results offer for the first time an aptamer-based therapeutic approach to the treatment of Th17 cell-mediated autoimmune disorders. |
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Authors:
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Akira Ishiguro; Taishin Akiyama; Hironori Adachi; Jun-Ichiro Inoue; Yoshikazu Nakamura |
Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Arthritis and rheumatism Volume: 63 ISSN: 1529-0131 ISO Abbreviation: Arthritis Rheum. Publication Date: 2011 Feb |
Date Detail:
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Created Date: 2011-01-31 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0370605 Medline TA: Arthritis Rheum Country: United States |
Other Details:
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Languages: eng Pagination: 455-66 Citation Subset: AIM; IM |
Copyright Information:
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Copyright © 2011 by the American College of Rheumatology. |
Affiliation:
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University of Tokyo, Tokyo, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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