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T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-\u03b3 and IL-10 by CD4+ T cells and IFN-\u03b3 by CD8+ T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4+ T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb-treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD.<\/jats:p>","DOI":"10.1093\/intimm\/dxt056","type":"journal-article","created":{"date-parts":[[2014,2,1]],"date-time":"2014-02-01T05:09:00Z","timestamp":1391231340000},"page":"369-381","source":"Crossref","is-referenced-by-count":4,"title":["The TIM-3 pathway ameliorates Theiler\u2019s murine encephalomyelitis virus-induced demyelinating disease"],"prefix":"10.1093","volume":"26","author":[{"given":"Tomoki","family":"Kaneyama","sequence":"first","affiliation":[{"name":"Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University 1 , Matsumoto, Nagano 390-8621 , Japan"},{"name":"Research Fellow of the Japan Society for the Promotion of Science, Chiyoda-ku, Tokyo 102-0083, Japan 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroki","family":"Tomiki","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University 1 , Matsumoto, Nagano 390-8621 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sayaka","family":"Tsugane","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University 1 , Matsumoto, Nagano 390-8621 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Inaba","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, School of Medicine, Shinshu University 3 , Matsumoto, Nagano 390-8621 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Motoki","family":"Ichikawa","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University 1 , Matsumoto, Nagano 390-8621 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hisaya","family":"Akiba","sequence":"additional","affiliation":[{"name":"Department of Immunology, Juntendo University Graduate School of Medicine 4 , Bunkyo-ku, Tokyo 113-8421 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideo","family":"Yagita","sequence":"additional","affiliation":[{"name":"Department of Immunology, Juntendo University Graduate School of Medicine 4 , Bunkyo-ku, Tokyo 113-8421 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung S.","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Microbiology-Immunology, Northwestern University Finberg Medical School 5 , Chicago, IL 60611 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chang-Sung","family":"Koh","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Sciences, Graduate School of Medicine, Shinshu University 1 , Matsumoto, Nagano 390-8621 , Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,1,31]]},"reference":[{"key":"2022072023084025600_CIT0001","doi-asserted-by":"crossref","first-page":"942","DOI":"10.1056\/NEJMra052130","article-title":"Multiple sclerosis\u2013the plaque and its pathogenesis","volume":"354","author":"Frohman","year":"2006","journal-title":"N. 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Med"},{"key":"2022072023084025600_CIT0008","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1038\/nm1297-1394","article-title":"Association of human herpes virus 6 (HHV-6) with multiple sclerosis: increased IgM response to HHV-6 early antigen and detection of serum HHV-6 DNA","volume":"3","author":"Soldan","year":"1997","journal-title":"Nat. Med"},{"key":"2022072023084025600_CIT0009","doi-asserted-by":"crossref","first-page":"1507","DOI":"10.1128\/jvi.61.5.1507-1516.1987","article-title":"Analysis of the complete nucleotide sequence of the picornavirus Theiler\u2019s murine encephalomyelitis virus indicates that it is closely related to cardioviruses","volume":"61","author":"Pevear","year":"1987","journal-title":"J. Virol"},{"key":"2022072023084025600_CIT0010","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0022-510X(76)90267-7","article-title":"Chronic neurologic disease in Theiler\u2019s virus infection of SJL\/J mice","volume":"30","author":"Lipton","year":"1976","journal-title":"J. Neurol. Sci"},{"key":"2022072023084025600_CIT0011","first-page":"497","article-title":"Multiple sclerosis. Animal model: Theiler\u2019s virus infection in mice","volume":"88","author":"Dal Canto","year":"1977","journal-title":"Am. J. 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Res"},{"key":"2022072023084025600_CIT0018","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1038\/415536a","article-title":"Th1-specific cell surface protein Tim-3 regulates macrophage activation and severity of an autoimmune disease","volume":"415","author":"Monney","year":"2002","journal-title":"Nature"},{"key":"2022072023084025600_CIT0019","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1084\/jem.20060210","article-title":"Dysregulated T cell expression of TIM3 in multiple sclerosis","volume":"203","author":"Koguchi","year":"2006","journal-title":"J. Exp. Med"},{"key":"2022072023084025600_CIT0020","doi-asserted-by":"crossref","first-page":"1102","DOI":"10.1038\/ni988","article-title":"Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance","volume":"4","author":"Sabatos","year":"2003","journal-title":"Nat. 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Neurosci. Res"},{"key":"2022072023084025600_CIT0032","first-page":"504","article-title":"Detection of Theiler\u2019s virus RNA in mouse central nervous system by in situ hybridization","volume":"45","author":"Stroop","year":"1981","journal-title":"Lab. Invest"},{"key":"2022072023084025600_CIT0033","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1097\/00005072-199606000-00001","article-title":"Two models for multiple sclerosis: experimental allergic encephalomyelitis and Theiler\u2019s murine encephalomyelitis virus","volume":"55","author":"Tsunoda","year":"1996","journal-title":"J. Neuropathol. Exp. 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