ECDI Coupled Cells for Tolerance in Allogeniec Islet Cell Transplantation for T1D

摘要 同种异体胰岛细胞移植治疗1型糖尿病 如果无限期免疫抑制的有害影响可以显著改善， 特别是它们对细胞的直接毒性，可以消除。因此，简单而又 在这种自身免疫性糖尿病宿主中有效的供体特异性耐受诱导 非常可取。我们最近开发了一种新的耐受方案，使用静脉注射。 经化学交联剂处理的供体脾细胞的输注 Ethyl-3-(3‘-dimethylaminopropyl)-carbodiimide，或ECDI，并发现在没有 任何免疫抑制，这种疗法在诱导持久供者方面是高效的- 同种异体胰岛细胞移植中化学诱导的特异性耐受 (链脲佐菌素)糖尿病模型。同样，胰岛素等可溶性自身抗原 通过ECDI化学固定在同基因抗原提呈细胞上已经独立 显示在自身免疫性糖尿病NOD模型中诱导强大的自我耐受性。 然而，在将这种方法转化为模型方面存在相当大的障碍 同时具有同种异体免疫和自身免疫，即在同种异体胰岛移植中 糖尿病NOD小鼠，一种临床上与1型患者高度相关的模型 糖尿病患者接受已故供者胰岛移植。此应用程序建议 采用集成方法确定关键的蜂窝组件和信令 此协议所需的耐受性路径以及存在的关键差异 在自身免疫节点中，宿主对无效的耐受诱导负有责任。这个 应用程序进一步建议在新的胰岛路线的背景下研究容差 可能在人类临床上适用的同种异体移植。的最终目标是 这项研究是为了设计出适合胰岛具体情况的新的耐受方案 人同种异体胰岛细胞移植是有效且临床可行的 移植。成功完成拟议的研究将具有重大意义 对1型糖尿病患者治疗选择的影响。

Abstract Human allogeneic islet cell transplantation as a therapy for cure for type 1 diabetes can be significantly improved if the deleterious effects of indefinite immunosuppression, particularly with their direct toxicity to ¿ cells, can be eliminated. Therefore, simple and effective donor-specific tolerance induction in such autoimmune diabetic hosts would be highly desirable. We have recently developed a novel tolerance regimen using i.v. infusion of donor splenocytes that are treated with a chemical cross-linker termed 1- ethyl-3-(3'-dimethylaminopropyl)-carbodiimide, or ECDI, and found that in the absence of any immunosuppression, this regimen is highly efficient in inducing durable donor- specific tolerance in allogeneic islet cell transplantation in the chemically-induced (streptozotocin) diabetes model. Similarly, soluble self-antigens such as insulin chemically fixed to syngeneic antigen presenting cells by ECDI have been independently shown to induce robust self-tolerance in the autoimmune diabetes NOD model. However, considerable obstacles exist in translating this methodology to a model harboring both alloimmunity and autoimmunity, i.e. in allogeneic islet transplantation for diabetic NOD mice, a model that is highly clinically relevant to patients with type 1 diabetes receiving deceased donor islet transplantation. This application proposes to take an integrated approach to identify crucial cellular components and signaling pathways required for tolerance by this protocol, as well as critical differences that exist in the autoimmune NOD hosts responsible for the ineffective tolerance induction. The application further proposes to study tolerance in the context of novel routes for islet allograft delivery that are potentially clinically applicable in humans. The ultimate goal of this study is to engineer novel tolerance regimen that is tailored to the specifics of islet allograft delivery, and is efficient and clinically feasible for human allogeneic islet cell transplantation. Successful completion of the proposed study will have significant impact on therapeutic options for patients with type 1 diabetes.