Marzorati S, Bocca N, Molano R D, Hogan A R, Doni M, Cobianchi L, Inverardi L, Ricordi C, Pileggi A
Diabetes Research Institute, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.
Transplant Proc. 2009 Jan-Feb;41(1):352-3. doi: 10.1016/j.transproceed.2008.09.057.
The aim of this study was to explore the effect of sirolimus (Sir) and tacrolimus (Tac) on islets implanted into a subcutaneous (SC), prevascularized device in syngeneic rats. Animals received a 40-day treatment with Tac and Sir (alone or in combination) starting either on day 0 or 40 days after islet transplantation. Controls received no treatment. A 40-day washout period was performed after immunosuppression (IS). Glycemia and intravenous glucose tolerance tests (IVGTT) were assessed at follow-up. In the control group, 75% of recipients achieved stable normoglycemia after islet transplantation, while none reversed diabetes with any IS regimen started on day 0. Graft dysfunction was irreversible after IS withdrawal. Glucose clearance (IVGTT) was significantly impaired among Tac-treated compared with control groups (P < .05 with IS; P < .01 after washout). Among animals with established grafts, islet dysfunction which occurred under IS treatment persisted after washout in animals treated with Tac and Sir plus Tac. When compared with controls, glucose clearance was significantly impaired in the Tac and Tac plus Sir groups before and after IS (P < .01, Tac; P < 0.01, Tac plus Sir). Sir and Tac showed profound deleterious effects on islet cell engraftment and function, which may hinder the success of implantation into biohybrid devices. Nondiabetogenic IS protocols must be developed for clinical application of islet transplantation into biohybrid devices.
本研究的目的是探讨西罗莫司（Sir）和他克莫司（Tac）对植入同基因大鼠皮下预血管化装置中的胰岛的影响。动物在胰岛移植后第0天或第40天开始接受为期40天的Tac和Sir（单独或联合使用）治疗。对照组不接受治疗。免疫抑制（IS）后进行40天的洗脱期。随访时评估血糖和静脉葡萄糖耐量试验（IVGTT）。在对照组中，75%的受体在胰岛移植后实现了稳定的正常血糖，而在第0天开始使用任何IS方案的情况下，没有一只受体逆转糖尿病。停用IS后移植物功能障碍是不可逆的。与对照组相比，Tac治疗组的葡萄糖清除率（IVGTT）显著受损（IS时P < 0.05；洗脱后P < 0.01）。在已建立移植物的动物中，在用Tac和Sir加Tac治疗的动物中，IS治疗期间发生的胰岛功能障碍在洗脱后仍然存在。与对照组相比，Tac组和Tac加Sir组在IS前后的葡萄糖清除率均显著受损（Tac组P < 0.01；Tac加Sir组P < 0.01）。Sir和Tac对胰岛细胞植入和功能显示出严重的有害影响，这可能会阻碍植入生物混合装置的成功。必须开发非致糖尿病的IS方案用于胰岛移植到生物混合装置的临床应用。
