Regulatory T cells to promote mixed chimerism for tolerance to islets and kidneys from deceased and living donors

调节性 T 细胞促进混合嵌合，以耐受死者和活体捐赠者的胰岛和肾脏

• 批准号: 9752451
• 负责人: Megan Sykes
• 金额: $ 204.79万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-18 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9752451
• 关键词: Achievement; Allogenic; Allograft Tolerance; Animal Model; Animals; Autoimmune Process; Autoimmunity; Biological Assay; Blood Vessels; Blood donor; Bone Marrow; Cells; Child; Chimerism; Clinical; Clone Cells; Communication; Cryopreservation; Development; Diabetic Nephropathy; Donor person; Drug toxicity; End stage renal failure; Goals; Hematopoietic; Hour; Human; Immunosuppression; Inbred NOD Mice; Insulin; Insulin-Dependent Diabetes Mellitus; Ischemia; Islets of Langerhans Transplantation; Kidney; Kidney Failure; Kidney Transplantation; Living Donors; Macaca fascicularis; Macaca mulatta; Modeling; Monkeys; Pancreatectomy; Parents; Patients; Phenotype; Population; Protocols documentation; Readiness; Recurrence; Regimen; Regulatory T-Lymphocyte; Research Proposals; Site; Source; Specimen; Supplementation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic immunosuppression; Toxic effect; Translating; Transplant Recipients; Transplantation; allograft rejection; base; biobank; conditioning; curative treatments; data management; design; diabetic patient; effector T cell; hematopoietic cell transplantation; islet; islet allograft; isoimmunity; kidney allograft; novel; offspring; preclinical study; prevent; sequencing platform; tool

This U19 proposal aims to achieve islet and kidney allograft tolerance through mixed chimerism in two complementary cynomolgus monkey projects that are supported by three cores. Both projects have relevance for end-stage renal disease (ESRD) and curative therapy for Type 1 diabetes (T1D). They employ related approaches to achieve tolerance for deceased and living donor grafts, respectively. Project 1 aims to use expanded polyclonal recipient Tregs to develop a compressed conditioning regimen that induces tolerance of simultaneous bone marrow, kidney and islet allografts from deceased donors. We have previously used a 6- day conditioning protocol that is relevant only for living donors, to achieve transient chimerism and kidney allograft tolerance in monkeys and humans. We now aim to develop a conditioning protocol that could be initiated after identification of a deceased donor, allowing transplantation (Tx) within 24 hours. Our approach builds on our demonstration that expanded polyclonal recipient Tregs can achieve far more prolonged chimerism and more robust tolerance than has previously been possible in the cynomolgus model. Tolerance obviates the need for long-term immunosuppressive therapy with its destructive effects on islet grafts. Moreover, our studies in NOD mice have shown that non-myeloablative induction of durable mixed chimerism reverses advanced anti-islet autoimmunity, simultaneously avoiding the alloimmunity, autoimmunity and drug toxicity that currently limit the efficacy of islet Tx in T1D. Project 2 aims to develop a tolerance induction strategy for curative treatment of end-stage diabetic nephropathy using living related donor (LRD) composite Islet-Kidney (IK) Tx. The project builds on our observation that transplanting pre-vascularized islets as part of composite IKs in large animal models requires far fewer islets to achieve insulin independence than Tx of free, non-vascularized islets. We recently achieved tolerance of IKs in rhesus monkeys using a novel, low intensity, hematopoietic cell transplant protocol in a “parent-to-offspring” combination. Project 2 aims to adjust components of the conditioning regimen and/or donor cell source that may have an early negative impact on islet function. Taking advantage of the ability to generate potent donor-specific Tregs prior to LRD Tx, we will test the ability of these cells to promote durable mixed allogeneic chimerism, with its potential to reverse T1D. Both projects will include extensive mechanistic analyses that build on a high-throughput TCR sequencing-based approach for tracking the alloreactive T cell repertoire that we have developed in humans and will apply to cynomolgus monkeys in Core B. Thus, we aim to achieve durable mixed chimerism in both projects to cure autoimmunity while simultaneously preventing alloimmune attack by inducing tolerance. Core A will provide monkey islets for both projects and Core B will develop a high throughput T cell receptor (TCR) sequencing platform that will be used to identify and track the fate of donor-specific alloreactive T cell clones, providing a unique mechanistic tool to be applied in both projects. Core C will provide administrative, biorepository and data management support for all of the projects and cores.

该 U19 提案旨在通过两种细胞的混合嵌合实现胰岛和肾同种异体移植耐受 由三个核心支持的互补食蟹猴项目两个项目都具有相关性。 用于终末期肾病 (ESRD) 和 1 型糖尿病 (T1D) 的治疗。 项目 1 旨在分别使用实现对死者和活体捐赠者移植物耐受的方法。 扩展多克隆受体Tregs以开发压缩调理方案，诱导耐受 我们之前使用过来自已故捐赠者的同步骨髓、肾脏和胰岛同种异体移植物。 仅与活体捐赠者相关的日间调理方案，以实现短暂嵌合和肾脏 我们现在的目标是开发一种可以启动的调节方案。 在确认已故捐赠者身份后，允许在 24 小时内进行移植 (Tx)。 我们证明，扩展的多克隆受体 Tregs 可以实现更长的嵌合状态以及更多 比以前在食蟹猴模型中可能具有的更强的耐受性消除了对食蟹猴模型的需要。 长期免疫抑制治疗对胰岛移植物具有破坏性作用此外，我们对 NOD 的研究。 小鼠表明，持久混合嵌合的非清髓性诱导可逆转高级抗胰岛细胞 自身免疫，同时避免目前限制的同种免疫、自身免疫和药物毒性 胰岛 Tx 在 T1D 中的功效 项目 2 旨在开发一种耐受诱导策略来治疗 T1D。 使用活体相关供体 (LRD) 复合胰岛肾 (IK) Tx 治疗终末期糖尿病肾病。 基于我们的观察，即在大型动物中移植预血管化胰岛作为复合 IK 的一部分 与游离的非血管化胰岛 We 相比，模型需要更少的胰岛来实现胰岛素独立。 最近使用新型低强度造血细胞移植在恒河猴中实现了 IK 耐受 项目 2 旨在调整调节方案的组成部分。 和/或可能对胰岛功能产生早期负面影响的供体细胞来源。 为了在 LRD Tx 之前生成有效的供体特异性 Tregs，我们将测试这些细胞促进持久性的能力 混合同种异体嵌合体，具有逆转 T1D 的潜力，这两个项目都将包括广泛的机制。 基于高通量 TCR 测序方法的分析，用于追踪同种异体反应性 T 细胞 我们在人类身上开发的全部功能，并将应用于核心 B 中的食蟹猴。因此，我们的目标 在两个项目中实现持久的混合嵌合，以治愈自身免疫，同时预防 通过诱导耐受性进行同种免疫攻击，核心 A 将为这两个项目提供猴岛，而核心 B 将为这两个项目提供猴岛。 开发高通量 T 细胞受体 (TCR) 测序平台，用于识别和跟踪 供者特异性同种反应性 T 细胞克隆的命运，提供了可应用于这两个项目的独特机制工具。 核心 C 将为所有项目和核心提供行政、生物样本库和数据管理支持。