Preclinical Studies of Living Donor Islet-Kidney Allograft Tolerance

活体胰岛肾同种异体移植物耐受性的临床前研究

• 批准号: 10216979
• 负责人: KAZUHIKO YAMADA
• 金额: $ 65.15万
• 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/10216979
• 关键词: Achievement; Age; Allogenic; Allograft Tolerance; Animal Model; Animals; Anti-CD40; Autoimmune; Autoimmune Diabetes; Autoimmune Responses; Autoimmunity; Autologous; Blood Vessels; CD34 gene; Cells; Child; Chimerism; Chronic; Clinical; Collaborations; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Dose; End stage renal failure; Fc Receptor; Goals; Hematopoietic; Hematopoietic stem cells; Homologous Transplantation; Immunosuppression; Inbred NOD Mice; Inflammatory; Inflammatory Response; Injections; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin 6 Receptor; Islet Cell; Islets of Langerhans Transplantation; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Life; Living Donors; Macaca mulatta; Measures; Mediating; Miniature Swine; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mothers; Mus; Onset of illness; Pancreas; Pancreatectomy; Papio; Parents; Patients; Phase; Prevalence; Protocols documentation; Recurrence; Regimen; Regulatory T-Lymphocyte; Renal Glycosuria; Reporting; Research Proposals; Sirolimus; Source; Supplementation; T cell receptor repertoire sequencing; T-Cell Depletion; T-Lymphocyte; Therapeutic immunosuppression; Time; Toxic effect; Translating; Transplantation; United States; Vascularization; Whole-Body Irradiation; base; capsule; clinical application; clinically relevant; conditioning; curative treatments; cytokine; design; diabetic; diabetic patient; diabetogenic; effector T cell; graft function; hematopoietic cell transplantation; human data; immunoregulation; improved; islet; isoimmunity; kidney allograft; mortality; mouse model; nonhuman primate; novel; offspring; post-transplant; potential biomarker; pre-clinical; preclinical study; predictive marker; preservation; prevent; response; stem cell engraftment; transplantation therapy

Project Summary: Project 2 is specifically designed toward the development of a tolerance induction strategy for curative treatment of end-stage diabetic nephropathy, using living donor composite Islet-Kidney (IK) transplantation (Tx). Many diabetic patients in renal failure, especially children, have potential donors willing to provide both a kidney and islets for transplantation. Unfortunately, the quantity of islets obtained through partial pancreatectomy from living donors is often insufficient to achieve insulin independence following isolated islet Tx. We have previously demonstrated that the strategy of 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. Both renal and islet function were restored by IK tx across fully allogeneic barriers in nephrectomized diabetic baboons using a clinically relevant immunosuppression protocol. More recently, we reported the successful induction of tolerance of IKs in rhesus monkeys using a novel, reduced intensity, hematopoietic cell Tx protocol in a “parent-to-offspring” combination. These data demonstrated “proof of principle” for the approach of induction of tolerance of allogeneic islet-kidneys. However, although allograft tolerance was achieved, chimerism was transient and insulin supplementation was required early post transplantation. We hypothesize that components of the conditioning regimen and/or donor cell source may have had an early negative impact on islet function. We also hypothesize that induction of tolerance through durable mixed chimerism may be more effective than transient chimerism in reversing autoimmunity associated with T1D, as has been demonstrated recently in an NOD mouse model. We therefore propose here to: 1) optimize the conditioning protocol and mobilized cell product in ways that are expected to improve preservation of islet function during the tolerance induction phase (Aim 1), including replacement of CyA with Rapamycin and anti-CD40 mAb and. If needed, use of purifed HSC; 2) add ex-vivo expanded donor-specific Tregs to the induction regimen, in order to facilitate the establishment of durable mixed chimerism (Aim 2). This approach is possible with the use of living-related donors, from whom one can generate donor-specific Tregs in advance of the transplant; and 3) study the fate of both effector and regulatory T cells in recipients of IKs (Aim 3), in order to determine the mechanism of tolerance and identify potential biomarkers predicting tolerance vs rejection. These studies will involve assessment of the deletion or expansion of effector and regulatory T cells using a high-throughput TCR sequencing approach developed in Core B. Islets will be provided by Core A and collaboration with Project 1 and both cores will be coordinated through Core C.

项目摘要：项目2专门设计用于制定宽容策略 用于治疗终阶段糖尿病性肾病的治疗 移植（TX）。许多肾衰竭的糖尿病患者，尤其是儿童，都有潜在的捐助者愿意 提供肾脏和胰岛进行移植。不幸的是，通过部分获得的胰岛数量 孤立的胰岛后，来自活供体的胰腺切除术通常不足以实现胰岛素独立性 TX。我们以前已经证明，移植前血管化胰岛的策略是 大型动物模型中的复合IK所需的胰岛较少才能实现胰岛素独立性，而不是自由的Tx 非血管化胰岛。肾功能和胰岛功能均由IK TX恢复在完全的同种异体障碍物中 使用临床相关的免疫抑制方案，肾切除型糖尿病狒狒。最近，我们 报道了使用新颖的强度降低的，成功地诱导IK在恒河猴中的耐受性， 造血细胞TX方案中的“父到源”组合。这些数据证明了“证明 原理”，用于诱导同种异体胰岛kidneys的耐受性。 实现了耐受性，嵌合是短暂的，需要提早补充胰岛素 移植。我们假设调理方案和/或供体细胞来源的组成部分 可能对胰岛功能产生了早期的负面影响。我们还假设诱导公差 通过耐用的混合嵌合物可能比瞬态嵌合在逆转时更有效 与T1D相关的自身免疫性，如最近在NOD小鼠模型中所证明的。我们 因此，此处提出建议：1）以类似的方式优化调理方案和动员细胞产品 预计将在耐受性诱导阶段提高胰岛功能的保存（AIM 1），包括 用雷帕霉素和抗CD40 mAb和。如果需要，使用净化的HSC； 2）添加前体 为了促进建立耐用的混合物 嵌合体（目标2）。使用与生活相关的捐助者可以从中产生这种方法 供体特异性treg在移植之前； 3）研究效应子和调节性T细胞的命运 IK的接受者（AIM 3），以确定耐受性的机制并识别潜在的生物标志物 预测公差与拒绝。这些研究将涉及评估效应子的缺失或扩展 使用高通量TCR测序方法在核心B中开发的高通量TCR测序方法和调节性T细胞将是 由核心A提供并与项目1合作，两个核心将通过CoreC进行协调。