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术和胰岛自体移植（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，我们位于南卡罗来纳州医科大学（MUSC）的中心已开展了100多例TP-IAT病例，预计根据我们目前的患者库，患者数量将不断增加。该手术的一个主要障碍是，与手术前>85%的无糖尿病率相比，TP-IAT后不到30%的患者成为胰岛素依赖型。在收获和移植后，胰岛细胞的急剧死亡损害了它们的功能。目前，没有干预方案的目的是增加TP-IAT患者胰岛自体移植物的存活率。因此，可以促进胰岛细胞植入并促进移植后存活的有效疗法是可行的。 不仅迫切需要预防CP患者TP-IAT后的术后糖尿病，而且可以潜在地作为一个平台，在其上解决1型糖尿病患者更复杂的同种异体胰岛细胞移植。越来越多的 文献表明，在小鼠和非人灵长类动物胰岛同种异体移植模型中，胰岛与间充质干细胞（MSC）一起移植增强了胰岛植入，通过促进细胞的功能和再生以及通过调节T细胞的功能来减少实现正常胰岛所需的胰岛数量。MSC可以离体增殖并且可以迁移到损伤部位（包括当体内静脉内注射时移植胰岛的肝脏）的事实使其成为胰岛自体移植的理想协同治疗选择。MSC目前正在20多项临床试验中进行测试，用于治疗1型和2型糖尿病及其相关并发症，这是基于其显着的免疫调节和再生特性。我们发现，小鼠胰岛与同基因间充质干细胞共培养可使其免于缺氧诱导的细胞凋亡，并增强其葡萄糖反应。然而，MSC在CP患者TP-IAT期间的保护作用还有待评估，这将是该资助的重点。基于来自其他人和我们组的当前数据，我们假设胰岛与离体扩增的自体MSC的共移植可以增强移植后的胰岛植入，导致更多CP患者在TP-IAT后无糖尿病。在这项研究中，我们将从CP患者中收获MSC，表征其表型，确认其在胰岛中的保护作用，并建立标准方案以收获临床级细胞。然后，我们将在一组患者中进行试点/可行性研究，以评估接受胰岛和自体MSC的患者在IAT后是否有更好的胰岛素非依赖性机会。根据我们在MUSC的积极胰岛移植计划，这种治疗程序可以很容易地转化为治疗，以造福患者护理。

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.