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

基本信息

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
项目类别：
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

项目摘要

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 专为制定耐受诱导策略而设计使用活体供体复合胰岛肾 (IK) 治疗终末期糖尿病肾病许多患有肾功能衰竭的糖尿病患者，尤其是儿童，都有愿意进行移植的潜在捐赠者。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。活体捐献者的胰腺切除术通常不足以实现孤立胰岛后的胰岛素独立性 Tx。我们之前已经证明了移植预血管化胰岛的策略作为大型动物模型中的复合 IK 需要比游离的 Tx 少得多的胰岛来实现胰岛素独立性，非血管化胰岛通过 IK tx 跨越完全同种异体屏障恢复了肾功能和胰岛功能。最近，我们使用临床相关的免疫抑制方案对糖尿病狒狒进行肾切除。报道了使用一种新颖的、降低强度的方法成功诱导了恒河猴的 IK 耐受性， “亲代到后代”组合中的造血细胞 Tx 协议这些数据证明了“证据”。 ” 对于同种异体胰岛肾的耐受原理的诱导方法，然而，尽管是同种异体移植。达到耐受性，嵌合现象是短暂的，需要在术后早期补充胰岛素我们采用了预处理方案和/或供体细胞来源的成分。我们还追踪到了耐受性的诱导。通过持久的混合嵌合可能比短暂的嵌合更有效地逆转与 T1D 相关的自身免疫，最近在 NOD 小鼠模型中得到了证实。因此，在此建议：1）以以下方式优化调节方案和动员细胞产物：预期在耐受诱导阶段（目标 1）改善胰岛功能的保存，包括用雷帕霉素和抗 CD40 mAb 替换 CyA，并且如果需要，使用纯化的 HSC 2) 离体添加；将供体特异性 Tregs 扩展到诱导方案中，以促进持久混合的建立嵌合现象（目标 2）可以通过使用与生俱来的捐赠者来实现，从这些捐赠者身上可以产生嵌合现象。移植前供体特异性 Tregs；3) 研究效应 T 细胞和调节性 T 细胞的命运 IK 接受者（目标 3），以确定耐受机制并识别潜在的生物标志物预测耐受性与排斥性这些研究将涉及效应子的删除或扩展的评估。和调节性 T 细胞，使用 Core B 中开发的高通量 TCR 测序方法。胰岛将被由核心 A 提供并与项目 1 协作，两个核心将通过核心 C 进行协调。