Treatment of Type I Diabetes by Islet Transplantation into the Gastric Submucosa

描述(申请人提供)：胰岛移植提供了一种微创的方法来恢复1型糖尿病患者的正常血糖，同时避免了强化胰岛素治疗中观察到的低血糖并发症和与胰腺移植相关的外科并发症。尽管在临床胰岛移植方面取得了重大进展，但总体结果仍然不理想，因为许多患者在移植后几年内失去了胰岛素独立性，通常需要多个供体才能实现独立。这种进行性功能丧失的原因是多因素的，但越来越多的证据表明，移植后胰岛的丧失很大程度上与临床胰岛移植中使用的门静脉内移植部位直接相关。胰岛的血管内输注会引发严重的非特异性炎症反应(即时血液介导的炎症反应，IBMIR)，破坏至少50%的胰岛质量。存活的胰岛的植入进一步受到相对低氧的门静脉环境的影响，并且注入的胰岛暴露在潜在的毒性水平下，免疫抑制剂从肠道吸收进入门静脉循环。这些特点共同导致了移植后胰岛功能的早期和晚期丧失。胃粘膜下层是一种新的移植部位，可以支持胰岛植入，同时避免了许多与门脉内输注相关的缺点。此外，通过上内窥镜可以很容易地进入这个部位，粘膜下注射程序安全且技术简单。这项前瞻性、单中心试验的目的是提供有关内窥镜下胃粘膜下胰岛移植治疗I型糖尿病患者肾移植安全性和有效性的初步临床经验。共有6名患者将被招募到试验中。我们将遵循标准化的胰岛制造方案和临床胰岛移植联盟(CIT)开发的基于胸球蛋白的诱导免疫抑制方案。结果将包括安全措施、血糖控制和胰岛素使用、移植物功能的代谢评估、同种/自身免疫反应，以及评估移植物排斥/炎症的方案活检。我们相信，这种新的胰岛移植方法有可能通过增强胰岛植入和长期功能来显著改善目前的胰岛移植结果。

DESCRIPTION (provided by applicant): Pancreatic islet transplantation offers a minimally invasive approach to restore normoglycemia in type 1 diabetics while avoiding the hypoglycemic complications observed with intensive insulin therapy and the surgical complications associated with pancreas transplantation. Although significant progress has been made in clinical islet transplantation, overall outcomes remain suboptimal since many patients lose insulin independence a few years after transplantation and multiple donors are usually needed to achieve independence. The cause of this progressive loss of function is multifactorial, but mounting evidence suggests that much of the islet loss after transplant is directly related to the intraportal transplant site that is used in clinical islet transplantation. Intravascular infusion f the islets triggers a severe, non-specific inflammatory response (immediate blood-mediated inflammatory reaction, IBMIR) which destroys at least 50% of the islet mass. The engraftment of the surviving islets is further compromised by the relatively hypoxic portal venous environment, and the infused islets are exposed to potentially toxic levels of immunosuppressive agents being absorbed from the gut into the portal circulation. Together, these characteristics contribute to early as well as late loss of islet function after transplantation. The gastric submucosa is a newl described transplant site that can support islet engraftment while avoiding many of the drawbacks associated with intraportal infusion. In addition, this site is easily accessible via upper endoscopy and the submucosal injection procedure is safe and technically straightforward. The aim of this prospective, single-center trial is to provide initial clinical experience regarding the safety and efficacy of endoscopic gastric submucosal islet transplantation in type I diabetic patients with kidney allografts. A total of 6 patients will be recruited into the trial. We will follow the standardized islet manufacturing protocols and the thymoglobulin-based induction immunosuppressive regimen developed by the Clinical Islet Transplant consortium (CIT). Outcomes will include safety measures, glycemic control and insulin use, metabolic assessments of graft function, allo/auto-immune responses, and protocol biopsies to assess graft rejection/inflammation. We believe that this novel approach to islet transplantation has the potential to significantly improve current islet transplantation outcomes by enhancing islet engraftment and long-term function.