Hering Bernhard J, Kandaswamy Raja, Ansite Jeffrey D, Eckman Peter M, Nakano Masahiko, Sawada Toshiya, Matsumoto Ippei, Ihm Sung-Hee, Zhang Hui-Jian, Parkey Jamen, Hunter David W, Sutherland David E R
Diabetes Institute for Immunology and Transplantation and Department of Surgery, University of Minnesota, Minneapolis 55455, USA.
JAMA. 2005 Feb 16;293(7):830-5. doi: 10.1001/jama.293.7.830.
Islet allografts from 2 to 4 donors can reverse type 1 diabetes. However, for islet transplants to become a widespread clinical reality, diabetes reversal must be achieved with a single donor to reduce risks and costs and increase the availability of transplantation.
To assess the safety of a single-donor, marginal-dose islet transplant protocol using potent induction immunotherapy and less diabetogenic maintenance immunosuppression in recipients with type 1 diabetes. A secondary objective was to assess the proportion of islet transplant recipients who achieve insulin independence in the first year after single-donor islet transplantation.
DESIGN, SETTING, AND PARTICIPANTS: Prospective, 1-year follow-up trial conducted July 2001 to August 2003 at a single US center and enrolling 8 women with type 1 diabetes accompanied by recurrent hypoglycemia unawareness or advanced secondary complications.
Study participants underwent a primary islet allotransplant with 7271 (SD, 1035) islet equivalents/kg prepared from a single cadaver donor pancreas. Induction immunosuppression was with antithymocyte globulin, daclizumab, and etanercept. Maintenance immunosuppression consisted of mycophenolate mofetil, sirolimus, and no or low-dose tacrolimus.
Safety (assessed by monitoring the severity and duration of adverse events) and efficacy (assessed by studying the recipients' insulin requirements, C-peptide levels, oral and intravenous glucose tolerance results, intravenous arginine stimulation responses, glycosylated hemoglobin levels, and hypoglycemic episodes) associated with the study transplant protocol.
There were no serious, unexpected, or procedure- or immunosuppression-related adverse events. All 8 recipients achieved insulin independence and freedom from hypoglycemia. Five remained insulin-independent for longer than 1 year. Graft failure in 3 recipients was preceded by subtherapeutic sirolimus exposure in the absence of measurable tacrolimus trough levels.
The tested transplant protocol restored insulin independence and protected against hypoglycemia after single-donor, marginal-dose islet transplantation in 8 of 8 recipients. These results may be related to improved islet engraftment secondary to peritransplant administration of antithymocyte globulin and etanercept. These findings may have implications for the ongoing transition of islet transplantation from clinical investigation to routine clinical care.
来自2至4个供体的胰岛同种异体移植可逆转1型糖尿病。然而，要使胰岛移植成为广泛的临床现实，必须通过单个供体实现糖尿病逆转，以降低风险和成本，并增加移植的可及性。
评估在1型糖尿病患者中使用强效诱导免疫疗法和致糖尿病作用较小的维持性免疫抑制的单供体、边缘剂量胰岛移植方案的安全性。次要目的是评估单供体胰岛移植后第一年实现胰岛素非依赖的胰岛移植受者比例。
设计、地点和参与者：2001年7月至2003年8月在美国一个中心进行的前瞻性1年随访试验，纳入8名伴有反复低血糖无知觉或晚期继发性并发症的1型糖尿病女性。
研究参与者接受了一次胰岛同种异体移植，移植的胰岛来自单一尸体供体胰腺，剂量为7271（标准差，1035）胰岛当量/千克。诱导免疫抑制采用抗胸腺细胞球蛋白、达利珠单抗和依那西普。维持性免疫抑制包括霉酚酸酯、西罗莫司，不使用或使用低剂量他克莫司。
与研究移植方案相关的安全性（通过监测不良事件的严重程度和持续时间进行评估）和疗效（通过研究受者的胰岛素需求、C肽水平、口服和静脉葡萄糖耐量结果、静脉精氨酸刺激反应、糖化血红蛋白水平和低血糖发作进行评估）。
没有严重、意外或与手术或免疫抑制相关的不良事件。所有8名受者均实现了胰岛素非依赖且无低血糖。5名受者保持胰岛素非依赖状态超过1年。3名受者出现移植物失败，之前西罗莫司暴露不足且他克莫司谷浓度不可测。
在8名受者中，所测试的移植方案在单供体、边缘剂量胰岛移植后恢复了胰岛素非依赖并预防了低血糖。这些结果可能与移植前给予抗胸腺细胞球蛋白和依那西普后胰岛植入改善有关。这些发现可能对胰岛移植从临床研究向常规临床护理的持续转变具有启示意义。
