Center for Transplantation Science, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
Woodruff School of Mechanical Engineering and Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, USA.
Sci Adv. 2022 May 13;8(19):eabm9881. doi: 10.1126/sciadv.abm9881.
Islet transplantation to treat insulin-dependent diabetes is greatly limited by the need for maintenance immunosuppression. We report a strategy through which cotransplantation of allogeneic islets and streptavidin (SA)-FasL-presenting microgels to the omentum under transient rapamycin monotherapy resulted in robust glycemic control, sustained C-peptide levels, and graft survival in diabetic nonhuman primates for >6 months. Surgical extraction of the graft resulted in prompt hyperglycemia. In contrast, animals receiving microgels without SA-FasL under the same rapamycin regimen rejected islet grafts acutely. Graft survival was associated with increased number of FoxP3 cells in the graft site with no significant changes in T cell systemic frequencies or responses to donor and third-party antigens, indicating localized tolerance. Recipients of SA-FasL microgels exhibited normal liver and kidney metabolic function, demonstrating safety. This localized immunomodulatory strategy succeeded with unmodified islets and does not require long-term immunosuppression, showing translational potential in β cell replacement for treating type 1 diabetes.
胰岛细胞移植治疗胰岛素依赖型糖尿病受到维持免疫抑制的极大限制。我们报告了一种策略，即将同种异体胰岛细胞和链霉亲和素（SA）-FasL 呈现微凝胶共移植到网膜下，在短暂雷帕霉素单药治疗下，导致糖尿病非人类灵长类动物的血糖控制良好，C 肽水平持续，移植物存活超过 6 个月。手术取出移植物会导致血糖迅速升高。相比之下，在相同雷帕霉素方案下接受无 SA-FasL 微凝胶的动物会急性排斥胰岛移植物。移植物的存活与移植物部位 FoxP3 细胞数量的增加有关，而对供体和第三方抗原的 T 细胞系统频率或反应没有显著变化，表明局部耐受。SA-FasL 微凝胶的接受者表现出正常的肝脏和肾脏代谢功能，证明其安全性。这种局部免疫调节策略成功地应用于未修饰的胰岛细胞，并且不需要长期免疫抑制，为治疗 1 型糖尿病的β细胞替代提供了转化潜力。
