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

虽然许多糖尿病肾功能衰竭患者，特别是儿童，有潜在的捐赠者愿意同时提供肾脏和胰岛，但实现胰岛素独立所需的胰岛数量阻碍了活体捐赠者部分胰腺切除的成功胰岛移植。项目2旨在开发一种耐受性诱导策略，用于使用活体供体复合胰岛-肾移植(TX)治疗终末期糖尿病肾病。我们先前已经证明，在大型动物模型中移植预血运胰岛作为IKS的一部分是成功的，使用的胰岛比移植自由的、非血运胰岛所需的胰岛要少得多。使用临床相关的免疫抑制方案，跨越完全同种异体屏障的肾脏和胰岛功能均通过肾切除糖尿病狒狒的IK-TX恢复。最近，我们的初步数据显示，在“母子”组合中，用造血细胞TX治疗恒河猴成功地诱导了iKs的耐受。为了将移植策略转化为临床应用，从而证明所需的额外供体风险是合理的 对于IK准备，本研究旨在通过我们以往的骨髓(BM)嵌合方案获得对IK的一致耐受诱导，以及确定成功的IK治疗所需的最小程度的胰腺切除。这些研究将使用循环系猴子和我们的BM TX条件化方案进行，该方案已被引入人类方案，并正在继续完善，以用于更广泛的临床应用(见本U19的项目1)。我们将首先确定是否可以在两种单倍型之间重复地诱导耐受和长期胰岛功能 和完全不匹配的障碍，以确定这一战略是否适用于活着的亲属和非亲属捐赠者组合(目标1)。然后，我们将评估重新移植到BM TX以进行耐受诱导的IK TX的最佳时机，以及评估IK准备所需的最小供体胰腺切除(AIM 2)。最后，我们将利用适当的策略，研究受者年龄、记忆T细胞(TMEM)和先天免疫反应对耐受诱导的影响，包括 胸腺再生、T-mem脱脂(与项目1结合)和抑制炎症(核心B)，以克服这些预期的障碍(目标3)。我们将研究适应性免疫因素和先天免疫因素在三个目标的合作中对耐受诱导的影响。与目前的临床治疗方法相比，这种方法在治疗终末期糖尿病肾病中的优势之一是，它将避免慢性免疫抑制的需要，避免与整个器官胰腺TX相关的发病率，并通过提供安全地从活体供者获得的有限胰岛体积的正常血糖来避免已故供者TX所需的漫长等待时间。

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" combinafion. In order to transifion 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 creafion. These studies will be carried out using cynomologous monkeys and our BM Tx condifioning 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 onehaplotype and fully mismatched barriers, in order to determine whether this strategy will be applicable for both living related and unrelated donor combinafions (Aim 1). We will then assess the optimal timing of IK Tx in relafion to BM Tx for tolerance inducfion, 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 inducfion of tolerance, utilizing appropriate strategies, including thymic rejuvenafion, T-mem deplefion (in conjucfion with Project 1) and inhibifion of inflammafion (Core B), respectively, to overcome these anticipated barriers (Aim 3). We will study the effects of adaptive and innate immune factors on tolerance inducfion in collaborafion with Project 3 for all three aims. Among the advantages of this approach in the treatment of end-stage diabefic 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 currenfiy required for deceased donor Tx by providing euglycemia with limited islet volume safely obtained from living donors.