title: Galectin-9 and T cell immunoglobulin mucin-3 pathway is a therapeutic target for type 1 diabetes.
abstract: Galectin-9 (Gal-9), a ligand for T cell Ig mucin-3 (Tim-3), induces apoptosis in cluster of differentiation 4 (CD4)(+) Tim-3(+) T helper 1 (T(H)1) cells via the Gal-9-Tim-3 pathway and negatively regulates T(H)1 immunity. In turn, Gal-9 activates dendritic cells (DC) to produce TNF-α, which promotes the T(H)1 response. We investigated the efficacy of Gal-9 against T(H)1-mediated autoimmune diabetes in NOD mice and compared with anti-Tim-3 monoclonal antibody (RMT3-23), which inhibited the binding between Tim-3-Ig and Gal-9 in a solid-phase binding assay. mRNA expression of Gal-9 was prominently induced by the treatment of interferon-γ in MIN6 cells, and Gal-9 was also expressed in the pancreatic β-cells in NOD mice, suggesting Gal-9 may be released from pancreatic β-cells to terminate T(H)1-mediated inflammation. Long-term injection of Gal-9 exhibits preventive efficacy for development of diabetes in NOD mice, but RMT3-23 demonstrated further prominent therapeutic potential compared with Gal-9. Gal-9 induced apoptosis of CD4(+)Tim-3(+) T(H)1 cells at the concentration of 0.2 μM, whereas RMT3-23 failed to enhance the apoptosis of CD4(+)Tim-3(+) T(H)1 cells. In contrast, Gal-9 induced TNF-α production in cultured DC in a dose-dependent manner; however, RMT3-23 inhibited Gal-9-induced TNF-α production in a dose-dependent manner. Although Gal-9 exhibited certain therapeutic potential against autoimmune diabetes by enhancing apoptosis of CD4(+)Tim-3(+) T(H)1 cells, RMT3-23 exhibited prominent therapeutic efficacy by suppressing the TNF-α production and activation of DC. Taken together, the inhibition of the Gal-9-Tim-3 pathway on DC, upstream of T(H)1 response, may be a new target for the treatment of type 1 diabetes.
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan.
authors.forename: Motoko
authors.initials: M
authors.lastname: Kanzaki
authors.forename: Jun
authors.initials: J
authors.lastname: Wada
authors.forename: Koichi
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Atsuko
authors.initials: A
authors.lastname: Nakatsuka
authors.forename: Sanae
authors.initials: S
authors.lastname: Teshigawara
authors.forename: Kazutoshi
authors.initials: K
authors.lastname: Murakami
authors.forename: Kentaro
authors.initials: K
authors.lastname: Inoue
authors.forename: Takahiro
authors.initials: T
authors.lastname: Terami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Katayama
authors.forename: Jun
authors.initials: J
authors.lastname: Eguchi
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D002478:Cells, Cultured; D003713:Dendritic Cells; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D005260:Female; D037161:Galectins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D016688:Mice, Inbred NOD; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011991:Receptors, Virus / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D037161:Galectins; C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D011991:Receptors, Virus; D014409:Tumor Necrosis Factor-alpha; C508186:galectin 9, mouse