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.
View: Text | PDF
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

×

Figure 1

Essential roles of HMGB1 in early loss of transplanted islets.

Options: View larger image (or click on image) Download as PowerPoint
Essential roles of HMGB1 in early loss of transplanted islets. (A) Nonfa...
(A) Nonfasting plasma glucose levels in STZ-induced diabetic mice received 200 syngeneic islets (top panel) and those treated with chicken anti-HMGB1 antibody or control chicken IgG. Individual lines represent glucose levels of each animal. (B) FACS profiles of liver MNCs from naive mice, STZ-induced diabetic mice that received 200 syngenic islets (Islet Tx), and islet transplanted mice treated with anti-HMGB1 antibody or with chicken IgG. NKT cells (top 2 rows) and Gr-1+CD11b+ cells (bottom 2 rows) were analyzed for IFN-γ (second and fourth rows). The numbers in the figures represent the percentage of cells in the corresponding square areas. Representative data from 4 experiments are shown. (C) FACS profiles of NKT cells and Gr-1+CD11b+ cells after HMGB1 treatment. Liver MNCs from wild-type or Jα18–/– mice treated with i.v. injection of saline or HMGB1 (100 μg/mouse) were isolated 2 hours after the injection and examined by flow cytometry for IFN-γ production by NKT cells and Gr-1+CD11b+ cells. The numbers in the figures represent the percentage of cells in the corresponding square areas. Representative data from 4 experiments are shown.