First Department of Surgery, Hokkaido University School of Medicine, Sapporo, Japan.
Transplantation. 2013 Sep 15;96(5):445-53. doi: 10.1097/TP.0b013e31829b0744.
Pancreatic islet transplantation (PITx) is an attractive treatment option for restoring appropriate glucose homeostasis in type 1 diabetes patients. Although islet grafts can successfully engraft after PITx, large numbers of islet grafts are required mainly because immune reactions, including inflammation, destroy islet grafts. In these processes, nuclear factor (NF)-κB plays a central role. We hypothesized that the inhibition of NF-κB activation would ameliorate inflammatory responses after PITx and aid successful engraftment.
To test this hypothesis, a newly developed NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), was used on a syngeneic mouse PITx model. One hundred seventy-five islets from C57BL/6 (B6) mice were transplanted into streptozotocin-induced diabetic B6 mice. The recipient mice were administered DHMEQ for 1, 2, or 3 days after PITx. The underlying mechanisms of DHMEQ on islet graft protection were investigated in an in vitro coculture model of pancreatic islets and macrophages.
With a vehicle treatment, only 11.1% of the islet-recipients achieved normoglycemia after PITx. In sharp contrast, DHMEQ treatment markedly improved the normoglycemic rate, which was associated with the suppression of serum high mobility group complex-1 (HMGB1) and proinflammatory cytokines, including tumor necrosis factor-α, monocyte chemoattractant protein-1, macrophage inflammatory protein-1β, interleukin-1β, and interleukin-6, after PITx. In a murine macrophage-like cell line, DHMEQ inhibited HMGB1-driven activation and proinflammatory cytokine secretion and further prevented death isolated islets after coculture with these activated macrophages.
Inhibition of NF-κB activation by DHMEQ after PITx reduces the HMGB1-triggered proinflammatory responses and results in engraftment of transplanted islets even with fewer islet grafts.
胰岛移植（PITx）是恢复 1 型糖尿病患者适当血糖稳态的一种有吸引力的治疗选择。尽管胰岛移植物在 PITx 后可以成功移植，但需要大量的胰岛移植物，主要是因为包括炎症在内的免疫反应会破坏胰岛移植物。在这些过程中，核因子（NF）-κB 起着核心作用。我们假设 NF-κB 激活的抑制会改善 PITx 后的炎症反应，并有助于成功移植。
为了验证这一假设，我们在同种异体小鼠 PITx 模型中使用了一种新开发的 NF-κB 抑制剂脱羟甲氧基环氧奎宁（DHMEQ）。将来自 C57BL/6（B6）小鼠的 175 个胰岛移植到链脲佐菌素诱导的糖尿病 B6 小鼠中。在 PITx 后，受体小鼠接受 DHMEQ 治疗 1、2 或 3 天。在胰岛和巨噬细胞的体外共培养模型中研究了 DHMEQ 对胰岛移植物保护的潜在机制。
在使用载体治疗的情况下，只有 11.1%的胰岛受者在 PITx 后实现了正常血糖。相比之下，DHMEQ 治疗显著提高了正常血糖率，这与抑制血清高迁移率族蛋白 1（HMGB1）和促炎细胞因子，包括肿瘤坏死因子-α、单核细胞趋化蛋白-1、巨噬细胞炎症蛋白-1β、白细胞介素-1β 和白细胞介素-6，在 PITx 后有关。在一种鼠巨噬细胞样细胞系中，DHMEQ 抑制了 HMGB1 驱动的激活和促炎细胞因子的分泌，并进一步防止了与这些激活的巨噬细胞共培养后分离的胰岛的死亡。
PITx 后 DHMEQ 抑制 NF-κB 激活可减少 HMGB1 触发的促炎反应，即使胰岛移植物数量较少，也能使移植的胰岛成功植入。
