Dissection on islet graft loss in association with engraftments in the liver

与肝脏植入相关的胰岛移植损失的解剖

• 批准号: 15390386
• 负责人: YASUNAMI Yohichi
• 金额: $ 8.45万
• 依托单位: Fukuoka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15390386/
• 关键词: islets; diabetes; rejection; engraftments; 移植膵島障害; NKT細胞; グラフト障害

Pancreatic islet transplantation has now become a procedure of choice for the treatment of insulin-dependent diabetes mellitus. Currently, however, the inability of achieving successful islet transplantation from one donor to one recipient is a major limiting factor, in which 2-3 cadaveric donor pancreases are required to cure a single recipient. Therefore, it is of quite significance to find a novel procedure to overcome the obstacle. In the present study, we focus on engraftments of islets into the liver, which is the site of clinical islet transplantation, facilitating to find a new way to minimize the number of donor islets required for successful transplantation.Vα14 NKT cells belong to a distinct subset of lymphocytes bridging the innate and acquired immune systems and play an important role in the immediate responses, because Vα14 NKT cells produce large amounts of IFN-γ immediately after activation. Since Vα14 NKT cells are relatively abundant in the liver, the site of choice for islet transplantation, and since IFN-γ is believed to be an important factor in the destruction of islet βcells, we hypothesized that Vα14 NKT cells in the liver might be involved in islet graft failure. We find that natural killer T(NKT)cells play an essential role in islet graft failure in mice and that a molecule responsible for the effect by NKT cells is INF-γ. The depletion of INF-γ releas from NKT cells of a recipient with α-galactosylceramide, a synthetic ligand of NKT cells, prior to islet transplantation produced successful transplantation with islets from a single donor pancreas. Thus, the present study elucidates a novel role of NKT cells in engraftments of islets and provides a potential that islet transplantation from one donor to one recipient, even to more than one, becomes feasible by targeting at NKT cells.

胰岛移植现已成为治疗胰岛素依赖型糖尿病的首选手术。然而，目前，无法实现从一个供体到一个受体的成功胰岛移植是主要的限制因素，其中需要2-3个尸体供体胰腺来治愈单个受体。因此，寻找一种新的程序来克服这一障碍具有重要意义。在本研究中，我们重点关注将胰岛移植到肝脏（临床胰岛移植的部位）中，以帮助找到一种新的方法来最大限度地减少成功移植所需的供体胰岛数量。Vα14 NKT细胞属于一个独特的淋巴细胞亚群，连接先天性和获得性免疫系统，并在立即反应中发挥重要作用，因为Vα14 NKT细胞在活化后立即产生大量IFN-γ。由于Vα14 NKT细胞在肝脏（胰岛移植的首选部位）中相对丰富，并且IFN-γ被认为是破坏胰岛β细胞的重要因素，因此我们假设肝脏中的Vα14 NKT细胞可能与胰岛移植失败有关。我们发现自然杀伤T（NKT）细胞在小鼠胰岛移植失败中起重要作用，并且负责NKT细胞作用的分子是INF-γ。在胰岛移植前，用α-半乳糖神经酰胺（一种NKT细胞的合成配体）去除受体NKT细胞中的INF-γ β，成功地用来自单个供体胰腺的胰岛移植。因此，本研究阐明了NKT细胞在胰岛移植中的新作用，并提供了一种潜力，即通过靶向NKT细胞，从一个供体到一个受体，甚至多个受体的胰岛移植变得可行。

项目成果

Beneficial Effects of Costimulatory Blockade with Anti-Inducilbe Costimulator Antibody in Conjunction with CTLA4Ig on Prevention of Islet Xenograft Rejection from Rat to Mouse.

使用抗诱导共刺激抗体联合 CTLA4Ig 进行共刺激阻断对预防大鼠至小鼠胰岛异种移植排斥的有益作用。

• 发表时间: 2004
• 期刊: Transplantation 78・11
• 作者: K Nabeyama;Y Yasunami;a Toyofuku;M Nakano;M Satoh;N Matsuoka;J Ono;M Kamada;T Uede;S Toda;S Ikeda.
• 通讯作者: S Ikeda.

E.Hirakawa, Y.Yasunami et al.: "Amelioration of hyperglycemia in streptozotocin-induced diabetic mice with fetal pancreatic allografts : prevention of rejection by donor specific transfusion in conjunction with CTLA4Ig."Pancreas. (in press).

E.Hirakawa、Y.Yasunami 等人：“用胎儿胰腺同种异体移植物改善链脲佐菌素诱导的糖尿病小鼠的高血糖：通过供者特异性输血结合 CTLA4Ig 预防排斥反应。”胰腺。