Prevention of High-Mobility Group Box 1-Mediated Early Loss of Transplanted Mouse Islets in the Liver by Antithrombin III.
Prevention of High-Mobility Group Box 1-Mediated Early Loss of Transplanted Mouse Islets in the Liver by Antithrombin III.
复制标题
抗凝血酶 III 预防肝脏中高迁移率组框 1 介导的移植小鼠胰岛的早期损失。
DOI：
10.1097/tp.0b013e31824d3508
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发表时间：
2012
期刊：
影响因子：
6.2
通讯作者：
Yasunami Y.
中科院分区：
文献类型：
--
作者：
Kojima D;Mera T;Nishinakamura H;Itoh T;Ogata T;Matsuoka N;Kodama S;Yasunami Y.
背景胰岛移植的低效率主要是由于移植胰岛的早期丢失而阻碍了其临床应用。之前，我们已经在小鼠中表明，肝脏中移植胰岛的早期丢失是由先天性免疫排斥反应引起的，与树突状细胞，自然杀伤T细胞和中性粒细胞一起产生干扰素（IFN）-γ，这是由移植胰岛释放的高迁移率族蛋白1（HMGB 1）触发的。我们在此确定是否HMGB 1介导的移植小鼠胰岛的早期损失是由抗凝血酶（ATIII）防止的MethodsThe效果ATIII在体外和体内HMGB 1刺激的IFN-γ产生的肝单核细胞进行了检查。然后，ATIII对链脲佐菌素诱导的糖尿病小鼠接受200个来自单个供体的同系胰岛的改善高血糖的效果determined.ResultsIn体外和体内的IFN-γ产生的单核细胞在小鼠的肝脏中响应HMGB 1被抑制ATIII。当在胰岛移植时给予ATIII而不是载体一次时，从单个供体接受200个同基因胰岛进入肝脏的链脲佐菌素诱导的糖尿病小鼠的高血压通过下调肝脏中自然杀伤T细胞和中性粒细胞的IFN-γ产生而得到改善。ATIII的良好效果同样实现在小鼠接受胰岛同种异体移植排斥反应时，防止与抗CD 4抗体treatment.ConclusionsThese研究结果表明，ATIII防止HMGB 1介导的先天性免疫排斥反应引起的移植胰岛的早期损失，这表明一个潜在的应用ATIII，以提高临床胰岛移植的效率。
BackgroundThe low efficiency of pancreatic islet transplantation mainly because of the early loss of transplanted islets hampers its clinical application. Previously, we have shown in mice that the early loss of transplanted islets in the liver is caused by innate immune rejection in concert with dendritic cells, natural killer T cells, and neutrophils to produce interferon (IFN)-γ, which is triggered by high-mobility group box 1 (HMGB1) released from transplanted islets. We herein determined whether the HMGB1-mediated early loss of transplanted mouse islets is prevented by antithrombin (ATIII).MethodsThe effect of ATIII on in vitro and in vivo HMGB1-stimulated IFN-γ production of hepatic mononuclear cells was examined. Then, the effect of ATIII on amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving 200 syngeneic islets from a single donor was determined.ResultsIn vitro and in vivo IFN-γ production of mononuclear cells in the liver of mice in response to HMGB1 was suppressed by ATIII. Hyperglycemia of streptozotocin-induced diabetic mice receiving 200 syngeneic islets into the liver from a single donor was ameliorated with down-regulation of IFN-γ production of natural killer T cells and neutrophils in the liver when ATIII but not vehicle was administered once at the time of islet transplantation. The favorable effect of ATIII was similarly achieved in mice receiving islet allografts when rejection was prevented with anti-CD4 antibody treatment.ConclusionsThese findings demonstrate that ATIII prevents HMGB1-mediated early loss of transplanted islets caused by innate immune rejection, suggesting a potential application of ATIII to improve efficiency of clinical islet transplantation.