Islet and Mesenchymal Stem Cell Co-transplantation Prevents Onset of Diabetes

描述(由申请人提供)：目前正在进行全胰腺切除和自体胰岛移植(TP-IAT)，以治疗选定的慢性胰腺炎(CP)患者的顽固性疼痛。自2009年以来，我们在南卡罗来纳医科大学(MUSC)的中心已经接受了100多例TP-IAT，基于我们目前的患者池，预计患者数量将会增加。这个过程中的一个主要障碍是，与手术前85%的无糖尿病患者相比，只有不到30%的患者在TP-IAT后达到胰岛素非依赖性。在收获和移植后，胰岛细胞戏剧性的死亡损害了它们的功能。目前，还没有旨在提高TP-IAT患者自体胰岛移植存活率的干预方案。因此，有效的治疗方法可以促进胰岛细胞植入并提高移植后的存活率 不仅是预防CP患者TP-IAT术后糖尿病的迫切需要，而且有可能成为解决1型糖尿病患者更复杂的同种异体胰岛细胞移植的平台。一群不断增加的 文献表明，在小鼠和非人灵长类胰岛移植模型中，胰岛与间充质干细胞(MSCs)联合移植可通过促进细胞的功能和再生以及调节T细胞的功能来增强胰岛植入，减少达到正常血糖所需的胰岛数量。MSCs可以在体外增殖并迁移到损伤部位，包括体内静脉注射胰岛时移植的肝脏，这使得它们成为自体胰岛移植的理想协同治疗选择。基于MSCs显著的免疫调节和再生特性，目前正在进行20多项临床试验，用于治疗1型和2型糖尿病及其相关并发症。我们发现，与同基因间充质干细胞共培养小鼠胰岛可以使它们免于缺氧诱导的细胞凋亡，并增强它们的葡萄糖反应。然而，骨髓间充质干细胞在CP患者TP-IAT中的保护作用尚未得到评估，这将是本次赠款的重点。根据前人和本组的研究结果，我们推测胰岛与体外扩增的自体MSCs共移植可以增强移植后胰岛的植入，从而使更多的CP患者在TP-IAT后无糖尿病。在这项研究中，我们将采集CP患者的MSCs，鉴定其表型，确认其在胰岛中的保护作用，并建立标准的采集方案，以获得临床级别的细胞。然后，我们将在一组患者中进行一项试点/可行性研究，以评估接受胰岛联合自体MSCs治疗的患者在IAT后是否有更好的机会实现胰岛素依赖。基于我们在MUSC的积极的胰岛移植计划，这一治疗过程可以很容易地转化为治疗，从而有利于患者的护理。

DESCRIPTION (provided by applicant): Total pancreatectomy and islet autotransplantation (TP-IAT) are currently being performed to treat intractable pain in selected patients with chronic pancreatitis (CP). Our center at the Medical University of South Carolina (MUSC) has undertaken more than 100 cases of TP-IAT since 2009, with the expectation of an increasing patient volume based on our current patient pool. A major hurdle in this procedure is that less than 30% of patients become insulin-independent after TP-IAT, compared to the >85% diabetes-free rate before surgery. A dramatic islet cell death during harvest and post-transplantation compromised their function. Currently, no interventional protocols are in place with the goal to increase the survival of islet autograft in TP-IAT patients. Thus, effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are not only urgently needed for the prevention of post-surgical diabetes after TP-IAT in CP patients, but can potentially serve as a platform on which to address the more complex allogeneic islet cell transplantation for patients with type 1 diabetes. An ever-increasing body of literature demonstrates that transplantation of islets together with mesenchymal stem cells (MSCs) enhances islet engraftment, decreases number of islets needed to achieve normoglycemia by promoting function and regeneration of ¿ cells and by modulating function of T cells in the mouse and nonhuman primates islet allogeneic transplantation models. The fact that MSCs can proliferate ex vivo and can migrate to the site of injury, including the liver where the islets are transplanted when injected intravenously in vivo, make them an ideal synergistic treatment option for islet autotransplantation. MSCs are currently being tested in more than 20 clinical trials for the treatment of type 1 and type 2 diabetes and their associated complications based on their remarkable immunoregulatory and regenerative properties. We have found that co-culturing mouse islets with syngeneic MSCs rescued them from hypoxia-induced apoptosis and enhanced their glucose response. However, the protective effects of MSCs during TP-IAT in CP patients has yet to be evaluated and will be the focus of this grant. Based on current data from others and our group, we hypothesize that co-transplantation of islets with autologous MSCs expanded ex vivo, can enhance islet engraftment after transplantation resulting in more CP patients being diabetes free after TP-IAT. In this study, we will harvest MSCs from CP patients, characterize their phenotype, confirm their protective effects in islets, and set up the standard protocol to harvest cells to clinical grade. We will then carry out a pilot/feasibility stdy in a group of patients to evaluate whether patients receiving islets together with autologous MSCs have a better chance of being insulin-independent after IAT. Based on our active islet transplantation program at MUSC, this treatment procedure can be readily translated into therapy to benefit patient care.