High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice
Nobuhide Matsuoka, … , Masaru Taniguchi, Yohichi Yasunami
Nobuhide Matsuoka, … , Masaru Taniguchi, Yohichi Yasunami
Published February 1, 2010
Citation Information: J Clin Invest. 2010;120(3):735-743. https://doi.org/10.1172/JCI41360.
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Research Article

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-γ 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-γ 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-γ 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

Nobuhide Matsuoka, Takeshi Itoh, Hiroshi Watarai, Etsuko Sekine-Kondo, Naoki Nagata, Kohji Okamoto, Toshiyuki Mera, Hiroshi Yamamoto, Shingo Yamada, Ikuro Maruyama, Masaru Taniguchi, Yohichi Yasunami

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Figure 5

Involvement of CD40-CD40L interaction in production of IL-12 and IFN-γ in early loss of transplanted islets.

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Involvement of CD40-CD40L interaction in production of IL-12 and IFN-γ i...
(A) CD40 expression in DCs and Neu before or after treatment with HMGB1. Liver MNCs (2 × 106) were treated without or with HMGB1 (20 μg/ml) for 24 hours and analyzed for CD40 expression (n = 3). (B) Requirement of CD40-CD40L interaction in the production of IL-12 and IFN-γ in the presence of NKT cells. DCs or Neu (4 × 104) were cocultured in vitro with NKT cells (2 × 105) in the presence of HMGB1 (20 μg/ml) for 48 hours with or without addition of anti-CD40L antibody. IL-12 and IFN-γ levels were measured by CBA (n = 3). The values are expressed as the mean ± SD. *P < 0.05; **P < 0.01. (C) Nonfasting plasma glucose levels of STZ-induced diabetic mice that had received 200 syngeneic islets and were treated with control goat IgG or goat anti-mouse IL-12 antibody and those with control hamster IgG or hamster anti-mouse CD40L antibody with 200 μg intraperitoneal injection per mouse at the time of transplantation. Individual lines represent the nonfasting plasma glucose levels of each diabetic mouse after islet transplantation.