Itoh Takeshi, Nitta Tomoyuki, Nishinakamura Hitomi, Kojima Daibo, Mera Toshiyuki, Ono Junko, Kodama Shohta, Yasunami Yohichi
From the *Department of Regenerative Medicine and Transplantation, Faculty of Medicine, Fukuoka University; and †Murakami Karindo Hospital, Fukuoka, Japan.
Pancreas. 2015 Jan;44(1):166-71. doi: 10.1097/MPA.0000000000000188.
The limited success in achieving insulin independence of patients with type 1 diabetes mellitus after islet transplantation from a single donor, mainly due to early loss of transplanted islets, hampers clinical application of islet transplantation. Previously, we have shown in mice that the early loss of transplanted islets in the liver, the site of islet transplantation, is caused by innate immune rejection triggered by high-mobility group box 1 (HMGB1) protein released from transplanted islets. We herein determined whether the HMGB1-mediated early loss of transplanted mouse islets is prevented by anti-interleukin-6 receptor (IL-6R) antibody.
The effect of anti-IL-6R antibody on amelioration of hyperglycemia in streptozocin-induced diabetic mice receiving 200 islets into the liver from a single donor was evaluated in association with HMGB1-stimulated interferon-γ production of hepatic mononuclear cells.
Hyperglycemia of diabetic mice receiving 200 syngeneic islets was ameliorated with down-regulation of interferon-γ production of hepatic natural killer T cells and neutrophils when anti-IL-6R was administered at the time of transplantation. This beneficial effect was also seen in allografts when alloimmune rejection was prevented by anti-CD4 antibody.
These findings demonstrate that anti-IL-6R antibody prevented the early loss of intrahepatic islet grafts with inhibiting HMGB1-induced immune activation after islet transplantation.
1型糖尿病患者接受单供体胰岛移植后实现胰岛素自主分泌的成功率有限,主要原因是移植胰岛早期丢失,这阻碍了胰岛移植的临床应用。此前,我们在小鼠中发现,胰岛移植部位肝脏中移植胰岛的早期丢失是由移植胰岛释放的高迁移率族蛋白B1(HMGB1)触发的先天性免疫排斥反应所致。我们在此确定抗白细胞介素-6受体(IL-6R)抗体是否能预防HMGB1介导的移植小鼠胰岛早期丢失。
在评估抗IL-6R抗体对链脲佐菌素诱导的糖尿病小鼠接受来自单供体的200个胰岛移植到肝脏后血糖改善情况时,检测其与HMGB1刺激的肝单核细胞产生干扰素-γ的相关性。
移植时给予抗IL-6R抗体,接受200个同基因胰岛的糖尿病小鼠的高血糖得到改善,肝自然杀伤T细胞和中性粒细胞产生的干扰素-γ减少。当用抗CD4抗体预防同种异体免疫排斥反应时,在同种异体移植中也观察到了这种有益效果。
这些发现表明,抗IL-6R抗体通过抑制胰岛移植后HMGB1诱导的免疫激活,预防了肝内胰岛移植物的早期丢失。