Satoh Masayuki, Yasunami Yohichi, Matsuoka Nobuhide, Nakano Masahiko, Itoh Takeshi, Nitta Tomoyuki, Anzai Keizo, Ono Junko, Taniguchi Masaru, Ikeda Seiyo
Department of Surgery, Fukuoka University, Fukuoka, Japan.
Transplantation. 2007 Apr 27;83(8):1085-92. doi: 10.1097/01.tp.0000260161.81775.58.
Currently, the inability to achieve successful islet transplantation from one donor to one recipient is a major obstacle facing clinical islet transplantation. We herein determined whether this limitation could be overcome by targeting pro-inflammatory cytokines with the prevention of immediate islet graft loss in association with engraftment in mice.
Isolated islets were grafted into the liver of streptozotocin-induced diabetic mice and the role of proinflammatory cytokines in the engraftment of islets was evaluated with the use of interferon (IFN)-gamma-/- mice and monoclonal antibodies against proinflammatory cytokines.
Hyperglycemia in streptozotocin-induced diabetic mice receiving 200 syngenic islets, which were isolated from a single mouse pancreas, was ameliorated when IFN-gamma-/-, but not wild-type mice, were used as recipients. The treatment with anti-IFN-gamma antibody produced normoglycemia in diabetic wild-type mice receiving 200, but not 100 islets. However, when anti-tumor necrosis factor-alpha and anti-interleukin-1beta antibodies were administered in conjunction with anti-IFN-gamma antibody, wild-type diabetic mice receiving 100 islets became normoglycemic after transplantation. In addition, the favorable effect of the combined use of antibodies was similarly achieved in mice receiving islet allografts when rejection was prevented with anti-CD4 antibody treatment.
These findings clearly demonstrate that successful islet transplantation from one donor to two recipients is feasible by targeting pro-inflammatory cytokines in mice, thus suggesting a potential application in clinical islet transplantation if similar mechanisms of islet graft loss could be mediated in humans.
目前，无法成功地将一个供体的胰岛移植给一个受体是临床胰岛移植面临的主要障碍。我们在此确定通过靶向促炎细胞因子并预防胰岛移植后立即丢失以及在小鼠体内实现植入，是否可以克服这一限制。
将分离的胰岛移植到链脲佐菌素诱导的糖尿病小鼠肝脏中，并使用干扰素（IFN）-γ-/-小鼠和抗促炎细胞因子单克隆抗体评估促炎细胞因子在胰岛植入中的作用。
当使用IFN-γ-/-小鼠而非野生型小鼠作为受体时，接受从一只小鼠胰腺分离的200个同基因胰岛的链脲佐菌素诱导的糖尿病小鼠的高血糖症得到改善。用抗IFN-γ抗体治疗使接受200个而非100个胰岛的糖尿病野生型小鼠血糖恢复正常。然而，当将抗肿瘤坏死因子-α和抗白细胞介素-1β抗体与抗IFN-γ抗体联合使用时，接受100个胰岛的野生型糖尿病小鼠移植后血糖恢复正常。此外，当用抗CD4抗体治疗预防排斥反应时，在接受胰岛同种异体移植的小鼠中同样实现了抗体联合使用的良好效果。
这些发现清楚地表明，通过靶向小鼠体内的促炎细胞因子，将一个供体的胰岛成功移植给两个受体是可行的，因此提示如果人类中也能介导类似的胰岛移植丢失机制，在临床胰岛移植中可能有潜在应用。
