Tolerance to Composite Islet-Kidney Transplants in Non-Human Primates

非人类灵长类动物对复合胰岛肾移植的耐受性

基本信息

批准号：
8725786
负责人：
KAZUHIKO YAMADA
金额：
$ 35.2万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8725786
关键词：
Adverse effects Affect Age Aging Allogenic Animal Model Autologous Biological Preservation Bone Marrow Cells Child Chimerism Chronic Clinical Management Clinical Protocols Collaborations Data Diabetes Mellitus Diabetic Nephropathy Down-Regulation End stage renal failure Haplotypes Hematopoietic Human Immune Immunosuppression Inflammation Injection of therapeutic agent Insulin Islet Cell Kidney Kidney Failure Kidney Transplantation Life Living Donors Macaca fascicularis Macaca mulatta Memory Methods Modality Modeling Monkeys Morbidity - disease rate Mothers Organ Pancreas Pancreas Transplantation Pancreatectomy Papio Pharmaceutical Preparations Preparation Procedures Protocols documentation Regimen Rejuvenation Reporting Research Proposals Risk Role Son Staging T memory cell Techniques Testing Time Toxic effect Translating Transplantation Vascularization Waiting Lists capsule clinical application clinically relevant conditioning design diabetic diabetic patient experience islet kidney allograft nonhuman primate novel pre-clinical prospective research study success type I diabetic

项目摘要

Although many diabetic patients in renal failure, especially children, have potential donors willing to provide both a kidney and islets, the quantity of islets necessary to achieve insulin independence hampers successful islet Tx by partial pancreatectomy from living donors. Project 2 is designed toward developing a tolerance-inducing strategy for curative treatment of end-stage diabetic nephropathy using living donor composite Islet-Kidney (IK) transplantation (Tx). We have previously demonstrated that the strategy of transplanting pre-vascularized islets as part of IKs in large animal models is successful, using far fewer islets than are required for 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, our preliminary data have shown the successful induction of tolerance of IKs in rhesus monkeys treated with hematopoietic cell Tx in a "mother-to-son" combination. In order to transition the IK strategy to clinical applicability, and thus justify the additional donor risk required for IK preparation, the present studies are directed toward achieving consistent tolerance induction to IKs with our historical bone marrow (BM) chimerism regimen, as well as determining the minimal degree of pancreatectomy required for successful IK creation. These studies will be carried out using cynomologous monkeys and our BM Tx conditioning regimen that has already been introduced into human protocols and continues to be refined for more widespread clinical application (see Project 1 of this U19). We will first determine whether tolerance and long-term islet function can be induced reproducibly across both one-haplotype and fully mismatched barriers, in order to determine whether this strategy will be applicable for both living related and unrelated donor combinations (Aim 1). We will then assess the optimal timing of IK Tx in relation to BM Tx for tolerance induction, as well as assess the minimal donor pancreatectomy required for IK preparation (Aim 2). Finally, we will examine the effects of recipient age, memory T-cells (Tmem), and innate immune reactivity on the induction of tolerance, utilizing appropriate strategies, including thymic rejuvenation, T-mem depletion (in conjunction with Project 1) and inhibition of inflammation (Core B), respectively, to overcome these anticipated barriers (Aim 3). We will study the effects of adaptive and innate immune factors on tolerance induction in collaboration with Project 3 for all three aims. Among the advantages of this approach in the treatment of end-stage diabetic nephropathy, in contrast to current clinical management, are that it would obviate the need for chronic immunosuppresion, avoid the morbidity associated with whole organ pancreas Tx, and circumvent the long wait list times currently required for deceased donor Tx by providing euglycemia with limited islet volume safely obtained from living donors.

尽管许多肾功能衰竭的糖尿病患者，尤其是儿童，都有愿意提供肾脏和胰岛的潜在捐赠者，但实现胰岛素独立所需的胰岛数量阻碍了通过活体捐赠者的部分胰腺切除术成功进行胰岛移植。项目 2 旨在开发一种耐受诱导策略，利用活体复合胰岛肾 (IK) 移植 (Tx) 来治愈终末期糖尿病肾病。我们之前已经证明，在大型动物模型中移植预血管化胰岛作为 IK 的一部分的策略是成功的，使用的胰岛数量远少于游离非血管化胰岛 Tx 所需的胰岛数量。使用临床相关的免疫抑制方案，IK Tx 跨越肾切除的糖尿病狒狒的完全同种异体屏障，恢复了肾脏和胰岛功能。最近，我们的初步数据显示，在“母子”组合中用造血细胞 Tx 治疗的恒河猴中成功诱导了 IK 耐受性。为了将 IK 策略转变为临床适用性，从而证明 IK 准备所需的额外供体风险是合理的，目前的研究旨在通过我们历史上的骨髓 (BM) 嵌合方案实现对 IK 的一致耐受诱导，并确定成功创建 IK 所需的最小程度的胰腺切除术。这些研究将使用食蟹猴和我们的 BM Tx 调理方案进行，该方案已被引入人类方案中，并继续完善以实现更广泛的临床应用（参见本 U19 的项目 1）。我们将首先确定是否可以跨单倍型和完全不匹配的障碍重复诱导耐受性和长期胰岛功能，以确定该策略是否适用于活体相关和无关的供体组合（目标 1）。然后，我们将评估 IK Tx 相对于 BM Tx 的最佳时机以进行耐受诱导，并评估 IK 准备所需的最小供体胰腺切除术（目标 2）。最后，我们将利用适当的策略，包括胸腺复兴、T-mem 耗竭（与项目 1 结合）和抑制，研究受体年龄、记忆 T 细胞 (Tmem) 和先天免疫反应性对诱导耐受的影响。炎症（核心 B），以克服这些预期的障碍（目标 3）。我们将与项目 3 合作，研究适应性和先天免疫因素对耐受诱导的影响，以实现所有三个目标。与目前的临床治疗相比，这种方法治疗终末期糖尿病肾病的优点包括无需长期免疫抑制，避免与全器官胰腺 Tx 相关的发病率，并避免漫长的等待名单通过提供从活体捐献者安全获得的有限胰岛体积的正常血糖，缩短了目前对已故捐献者 Tx 所需的时间。