Autologous BM-MSCs and Islet Co-transplantation to Enhance Islet Survival and Function in TP-IAT Patients

项目摘要： 全胰腺切除术和胰岛自体移植（TP-IAT）目前在大约20个中心进行 慢性胰腺炎（CP）的治疗。与TP-IAT相关的主要问题是胰岛功能不佳， 移植和门静脉内输注后功能障碍。由于这些问题，只有大约20%的非- 糖尿病CP患者在手术后不依赖胰岛素。目前，介入协议，以增加 移植后胰岛移植物的存活率是经验性的。因此，有效的治疗，可以促进胰岛 细胞移植和促进移植后的存活是迫切需要的。 包括我们自己的研究在内的多项研究表明，胰岛与间充质干细胞（MSC）共移植 增强胰岛植入，减少啮齿动物中达到正常血糖所需的胰岛数量， 非人灵长类胰岛移植模型。MSC主要通过直接的细胞-细胞接触发挥这种作用， 它们旁分泌保护性分子，包括胰岛素生长因子-1（IGF-1）、肝细胞生长 因子（HGF）、转化生长因子β（TGF- β）等。我们是第一个表演飞行员的团体 NIH资助的临床试验评估自体骨髓来源的体外扩增的MSC的可行性 （BM-MSCS）和胰岛共移植在CP患者中的应用。虽然只有三名受试者接受了MSC和胰岛联合治疗， 移植由于试点性质的赠款，我们的数据表明，骨髓间充质干细胞和胰岛共移植， 是一个安全和有前途的策略，以提高胰岛移植后的植入。基于这种独特的临床 试验经验和动物研究，本研究的目的是进一步评价 自体MSC和胰岛共移植在更大的TP-IAT患者群体中。我们的假设是- 用自体BM-MSC移植胰岛可以提高移植后胰岛的存活和功能， 导致更多的CP患者在TP-IAT后无糖尿病。这项试验的一个关键部分将是定义 MSC调节β细胞存活的机制，并探索可用于治疗的细胞和分子生物标志物。 用作β细胞死亡和MSC疗法的潜在反应/功效的指标。从这些 研究不仅迫切需要预防CP患者术后糖尿病，而且可能 提供有用的信息，以解决更复杂的同种异体胰岛细胞移植的患者 患有1型糖尿病

Project Summary: Total pancreatectomy and islet autotransplantation (TP-IAT) are currently performed in around 20 centers worldwide for the treatment of chronic pancreatitis (CP). Major problems associated with TP-IAT are poor islet engraftment and dysfunction after intraportal infusion. Because of these issues, only around 20% of the non- diabetic CP patients are insulin-independent after surgery. Currently, interventional protocols to increase the survival of the islet graft following transplantation are empiric. Thus, effective therapies that can facilitate islet cell engraftment and promote survival after transplantation are urgently needed. Multiple studies including our own demonstrate that islet co-transplantation with mesenchymal stem cells (MSCs) enhances islet engraftment, decreases number of islets needed to achieve normoglycemia in rodent and nonhuman primate islet transplantation models. MSCs exert such effects mainly via direct cell-cell contact and their paracrine secretion of protective molecules including insulin growth factor-1 (IGF-1), hepatocyte growth factor (HGF), transforming growth factor β (TGF- β) and others. We are the first group who performed a pilot NIH-funded clinical trial evaluating the feasibility of autologous bone marrow-derived ex vivo-expanded MSCs (BM-MSCS) and islet co-transplantation in CP patients. Although only three subjects received MSC and islet co- transplantation due to the pilot nature of the grant, our data showed that BM-MSCs and islet co-transplantation was a safe and promising strategy to improve islet engraftment after transplantation. Based on this unique clinical trial experience and animal studies, the goal of this study is to further evaluate the safety and efficacy of autologous MSCs and islet co-transplantation in a larger TP-IAT patient population. Our hypothesis is that co- transplantation of islets with autologous BM-MSCs can enhance islet survival and function after transplantation, resulting in more CP patients being diabetes free after TP-IAT. A critical part of this trial will be to define the mechanisms by which MSCs modulate β cell survival and explore cellular and molecular biomarkers that can be used as indicator(s) for β cell death and the potential response/efficacy of MSC therapy. Results from these studies are not only urgently needed for the prevention of post-surgical diabetes in CP patients, but also may offer useful information on which to address the more complex allogeneic islet cell transplantation for patients with type 1 diabetes.