Department of Regenerative Medicine and Transplantation, Fukuoka University, Japan.
J Clin Invest. 2010 Mar;120(3):735-43. doi: 10.1172/JCI41360.
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.
胰岛移植治疗 1 型糖尿病的临床应用受到限制，主要是由于移植的胰岛早期丢失，导致移植效率低下。Gr-1(+)CD11b(+)细胞中 NKT 细胞依赖性 IFN-γ产生对于这种丢失是必不可少的，但该过程中的上游事件仍未确定。在这里，我们已经证明，高迁移率族蛋白 B1（HMGB1）在糖尿病小鼠模型中移植胰岛早期丢失的初始事件中起关键作用。胰岛中含有丰富的 HMGB1，在胰岛移植到肝脏后不久就会释放到循环中。用 HMGB1 特异性抗体治疗可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 IFN-γ。此外，缺乏已知的 HMGB1 受体 TLR2 或晚期糖基化终产物受体（RAGE）的小鼠，但不缺乏已知的 HMGB1 受体 TLR4 的小鼠未能表现出早期胰岛移植物丢失。从机制上讲，HMGB1 在体内和体外刺激肝单核细胞（MNC）；特别是，它上调了 DC 中 CD40 的表达，并增强了 IL-12 的产生，导致 NKT 细胞激活，随后 Gr-1(+)CD11b(+)细胞产生 NKT 细胞依赖性增强的 IFN-γ。因此，用 IL-12 或 CD40L 特异性抗体治疗可防止早期胰岛移植物丢失。这些发现表明，HMGB1 介导的引发早期胰岛丢失的途径是改善胰岛移植效率的潜在干预靶点。
