日本醫(yī)學專家發(fā)現(xiàn)實驗鼠體內(nèi)的“HMGB1”蛋白與胰島細胞肝內(nèi)移植時發(fā)生的排異反應相關,。研究人員使用這種蛋白的抗體,，成功控制了實驗鼠在移植胰島細胞后的早期排異反應,。
日本福岡大學日前發(fā)表新聞公報說，日本國內(nèi)有糖尿病患者約890萬人,，其中約10萬人為終身需要接受胰島素注射的重癥患者,。而將分泌胰島素的胰島細胞移植到患者肝臟內(nèi)的所謂胰島細胞肝內(nèi)移植可有效幫助糖尿病重癥患者擺脫胰島素注射的痛苦。然而,，胰島細胞肝內(nèi)移植會引發(fā)排異反應,，特別是移植后幾小時內(nèi)發(fā)生的早期排異反應會嚴重影響移植效果。
福岡大學和理化研究所的研究人員借助糖尿病模型實驗鼠發(fā)現(xiàn),，移植后的胰島細胞會大量釋放“HMGB1”蛋白質(zhì),，這種蛋白一旦被釋放到細胞外，就會引發(fā)胰島細胞的早期排異反應,。
根據(jù)這一發(fā)現(xiàn),，研究人員開發(fā)出通過測定血液中“HMGB1”蛋白的含量來判定胰島細胞肝內(nèi)移植引發(fā)的早期排異反應發(fā)作的系統(tǒng)，并通過給實驗鼠使用“HMGB1”抗體,，成功避免了早期排異反應的發(fā)生,，使移植效率大大提高。
公報說,，類似機制同樣存在于人體,，因此使用“HMGB1”抗體應該也能提高人體移植胰島細胞的效率。該研究將刊登在３月號的美國《臨床檢查雜志》上,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
