High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice
High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice
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DOI：
10.1172/jci41360
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发表时间：
2010-03-01
影响因子：
15.9
通讯作者：
Yasunami, Yohichi
中科院分区：
文献类型：
--
作者：
Matsuoka, Nobuhide;Itoh, Takeshi;Yasunami, Yohichi
胰岛移植治疗1型糖尿病的临床应用受到限制，主要原因是移植胰岛早期丢失，移植效率低。依赖NKT细胞的Gr-1(+)CD11b(+)细胞产生的干扰素-γ是这种丢失的关键，但这一过程中的上游事件仍未确定。在这里，我们已经证明了高迁移率族蛋白1(HMGB1)在糖尿病小鼠模型移植胰岛早期丢失的初始事件中起着关键作用。胰岛含有丰富的HMGB1，在胰岛移植到肝脏后不久就被释放到循环中。用HMGB1特异性抗体治疗可以防止早期胰岛移植物丢失，并抑制NKT细胞和Gr-1(+)CD11b(+)细胞产生干扰素-γ。此外，缺乏已知的HMGB 1受体TLR2或晚期糖基化终产物受体(RAGE)，但没有已知的HMGB I受体TLR4的小鼠，未能表现出早期的胰岛移植物丢失。在体内和体外，HMGB1刺激肝脏单个核细胞(MNC)，特别是上调CD40的表达，促进DC产生IL-12，导致NKT细胞激活，随后Gr-1(+)CD11b(+)细胞依赖NKT细胞增加干扰素-γ的产生。因此，用IL-12或CD40L特异性抗体治疗可以防止早期胰岛移植物丢失。这些发现表明，HMGB1介导的早期胰岛丢失通路是提高胰岛移植效率的潜在干预靶点。
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 HMGB 1 receptors TLR2 or receptor for advanced glycation end products (RAGE), but not the known HMGB I 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.