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

ECDI 偶联细胞在 T1D 异体胰岛细胞移植中的耐受性

• 批准号: 8001130
• 负责人: Xunrong Luo
• 金额: $ 10万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8001130
• 关键词: Allogenic; Antigen-Presenting Cells; Autoantigens; Autoimmune Diabetes; Autoimmune Process; Autoimmunity; Carbodiimides; Cells; Chemicals; Coupled; Engineering; Goals; Human; Immunosuppression; Inbred NOD Mice; Infusion procedures; Insulin; Insulin-Dependent Diabetes Mellitus; Islets of Langerhans Transplantation; Methodology; Modeling; Patients; Protocols documentation; Regimen; Route; Self Tolerance; Signal Pathway; Splenocyte; Streptozocin Diabetes; Therapeutic; Toxic effect; Translating; abstracting; clinically relevant; diabetic; improved; islet allograft; isoimmunity; novel

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.

抽象的 人类同种异体胰岛细胞移植作为治疗1型糖尿病的疗法 如果不确定免疫抑制的删除效应，可以显着改善 特别是由于它们对细胞的直接毒性，可以消除。因此，简单 这种自身免疫性糖尿病宿主中有效的供体特异性耐受性诱导将是 非常可取。我们最近使用i.v.开发了一种新颖的耐受性方案。 输注用称为1-的化学交联处理的供体脾细胞 乙基-3-（3'-二甲基氨基丙基）-Carbodiimide或ECDI，发现在不存在的情况下 任何免疫抑制，该方案在诱导的持久供体中都高效 化学诱导的同种异体胰岛细胞移植中的特异性耐受性 （链蛋白酶）糖尿病模型。同样，固体自我抗原（如胰岛素） 通过ECDI的化学固定在同性抗原呈现细胞上已独立 显示出在自身免疫性糖尿病模型中诱导强大的自我耐受性。 但是，将这种方法转化为模型时存在很大的障碍 同时拥有同种异体和自身免疫性，即在同种异体胰岛移植中 糖尿病点头小鼠，该模型在临床上与1型患者高度相关 接受已故供体胰岛移植的糖尿病。此申请建议 采用集成方法来识别重要的细胞成分和信号传导 该协议所需的公差所需的途径以及存在的关键差异 在自身免疫性点头宿主中，负责无效的耐受性诱导。这 应用进一步的建议，以研究胰岛新颖路线的耐受性 同种异体移植物可能在临床上适用于人类。最终目标 这项研究是针对根据胰岛规格量身定制的新型耐受性方案 同种异体移植递送，并且对人类同种异体胰岛细胞有效且在临床上是可行的 移植。成功完成拟议的研究将具有重要的 对1型糖尿病患者的热选择的影响。