日本医学专家发现实验鼠体内的“HMGB1”蛋白与胰岛细胞肝内移植时发生的排异反应相关。研究人员使用这种蛋白的抗体，成功控制了实验鼠在移植胰岛细胞后的早期排异反应。
日本福冈大学日前发表新闻公报说，日本国内有糖尿病患者约890万人，其中约10万人为终身需要接受胰岛素注射的重症患者。而将分泌胰岛素的胰岛细胞移植到患者肝脏内的所谓胰岛细胞肝内移植可有效帮助糖尿病重症患者摆脱胰岛素注射的痛苦。然而，胰岛细胞肝内移植会引发排异反应，特别是移植后几小时内发生的早期排异反应会严重影响移植效果。
福冈大学和理化研究所的研究人员借助糖尿病模型实验鼠发现，移植后的胰岛细胞会大量释放“HMGB1”蛋白质，这种蛋白一旦被释放到细胞外，就会引发胰岛细胞的早期排异反应。
根据这一发现，研究人员开发出通过测定血液中“HMGB1”蛋白的含量来判定胰岛细胞肝内移植引发的早期排异反应发作的系统，并通过给实验鼠使用“HMGB1”抗体，成功避免了早期排异反应的发生，使移植效率大大提高。
公报说，类似机制同样存在于人体，因此使用“HMGB1”抗体应该也能提高人体移植胰岛细胞的效率。该研究将刊登在３月号的美国《临床检查杂志》上。（生物谷Bioon.com）
生物谷推荐原文出处：
J Clin Invest. 2010;120(3):735–743. doi:10.1172/JCI41360
High-mobility group box 1 is involved in the initial events of early loss of transplanted islets in mice
Nobuhide Matsuoka,1,2 Takeshi Itoh,1 Hiroshi Watarai,3 Etsuko Sekine-Kondo,3 Naoki Nagata,4 Kohji Okamoto,4 Toshiyuki Mera,1,2 Hiroshi Yamamoto,5 Shingo Yamada,6 Ikuro Maruyama,7 Masaru Taniguchi,3 and Yohichi Yasunami1
1Department of Regenerative Medicine and Transplantation and 2Department of Gastrointestinal Surgery, Faculty of Medicine, Fukuoka University, Japan.
3Laboratory for Immune Regulation, RIKEN Research Center for Allergy and Immunology, Yokohama, Japan. 4Department of Surgery 1,
University of Occupational and Environmental Health, School of Medicine, Kitakyushu, Japan. 5Department of Biochemistry and Molecular Vascular Biology,
Kanazawa University Graduate School of Medical Science, Japan. 6Shino-Test Co., Sagamihara, Japan. 7Department of Laboratory and Vascular Medicine,
Kagoshima University Graduate School of Medical and Dental Sciences, Japan.
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-γ 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-γ 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-γ 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.
