title: High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice.
abstract: Islet transplantation for the treatment of type 1 diabetes mellitus is limited in its clinical application mainly due to early loss of the transplanted islets, resulting in low transplantation efficiency. NKT cell-dependent IFN-gamma production by Gr-1(+)CD11b(+) cells is essential for this loss, but the upstream events in the process remain undetermined. Here, we have demonstrated that high-mobility group box 1 (HMGB1) plays a crucial role in the initial events of early loss of transplanted islets in a mouse model of diabetes. Pancreatic islets contained abundant HMGB1, which was released into the circulation soon after islet transplantation into the liver. Treatment with an HMGB1-specific antibody prevented the early islet graft loss and inhibited IFN-gamma production by NKT cells and Gr-1(+)CD11b(+) cells. Moreover, mice lacking either of the known HMGB1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB1 receptor TLR4, failed to exhibit early islet graft loss. Mechanistically, HMGB1 stimulated hepatic mononuclear cells (MNCs) in vivo and in vitro; in particular, it upregulated CD40 expression and enhanced IL-12 production by DCs, leading to NKT cell activation and subsequent NKT cell-dependent augmented IFN-gamma production by Gr-1(+)CD11b(+) cells. Thus, treatment with either IL-12- or CD40L-specific antibody prevented the early islet graft loss. These findings indicate that the HMGB1-mediated pathway eliciting early islet loss is a potential target for intervention to improve the efficiency of islet transplantation.
authors.affiliation: Department of Regenerative Medicine and Transplantation, Fukuoka University, Japan.
authors.forename: Nobuhide
authors.initials: N
authors.lastname: Matsuoka
authors.forename: Takeshi
authors.initials: T
authors.lastname: Itoh
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watarai
authors.forename: Etsuko
authors.initials: E
authors.lastname: Sekine-Kondo
authors.forename: Naoki
authors.initials: N
authors.lastname: Nagata
authors.forename: Kohji
authors.initials: K
authors.lastname: Okamoto
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Mera
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Shingo
authors.initials: S
authors.lastname: Yamada
authors.forename: Ikuro
authors.initials: I
authors.lastname: Maruyama
authors.forename: Masaru
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Yohichi
authors.initials: Y
authors.lastname: Yasunami
mesh_terms: D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D039481:CD11b Antigen / Q000235:genetics / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology; D007515:Islets of Langerhans / Q000276:immunology* / Q000473:pathology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology; D055611:Natural Killer T-Cells / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000819:agonists / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology
chemical_list: D000906:Antibodies; D039481:CD11b Antigen; D019013:CD40 Antigens; D024243:HMGB1 Protein; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; C498977:Mok protein, mouse; D020928:Mitogen-Activated Protein Kinases