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

自体 BM-MSC 和胰岛联合移植可增强 TP-IAT 患者的胰岛存活和功能

基本信息

批准号：
10315988
负责人：
Hongjun Wang
金额：
$ 63.22万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-24 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10315988
关键词：
Address Adverse event Allogenic Animals Area Under Curve Autologous Autologous Transplantation Beta Cell Bone Marrow C-Peptide Cell Culture Techniques Cell Death Cell Survival Cells Clinical Research Clinical Trials Complement Factor B Complex Constitution Cyclic GMP Cytoprotection DNA Data Diabetes Mellitus Disease Dose Engraftment Enzyme-Linked Immunosorbent Assay Flow Cytometry Functional disorder Funding Gene Expression Goals Grant Growth Factor HGF gene Human Immune response Inflammatory Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Intervention Islet Cell Islets of Langerhans Transplantation Measures Mediator of activation protein Mesenchymal Mesenchymal Stem Cells MicroRNAs Modeling Nature Operative Surgical Procedures Patient Recruitments Patients Prevention Production Protocols documentation Quality of life Randomized Controlled Clinical Trials Research Rodent Safety Serum Testing Therapeutic Total Pancreatectomy Transforming Growth Factors Translating Transplant Recipients Transplantation United States National Institutes of Health base bench to bedside chemokine chronic pancreatitis cytokine effective therapy experience glycemic control improved insight islet molecular marker monocyte non-diabetic nonhuman primate pain relief paracrine patient population post-transplant primary endpoint response secondary endpoint single-cell RNA sequencing stem cell therapy stem cells transplant model

项目摘要

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.

项目概要：目前约有 20 个中心进行全胰腺切除术和胰岛自体移植 (TP-IAT) 与 TP-IAT 相关的主要问题是胰岛质量较差。由于这些问题，只有约 20% 的非门静脉注射后会出现植入和功能障碍。糖尿病CP患者术后不依赖胰岛素。目前，介入治疗方案增加了胰岛素依赖性。移植后胰岛移植物的存活率是经验性的，因此，可以促进胰岛移植的有效疗法。迫切需要细胞植入并促进移植后的存活。包括我们自己在内的多项研究表明，胰岛与间充质干细胞 (MSC) 共移植增强胰岛移植，减少啮齿类动物达到正常血糖所需的胰岛数量非人灵长类胰岛移植模型主要通过直接细胞间接触和作用发挥这种作用。它们旁分泌分泌保护性分子，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）等我们是第一批进行试点的。 NIH 资助的临床试验评估自体骨髓来源的离体扩增 MSC 的可行性 (BM-MSCS) 和 CP 患者的胰岛联合移植尽管只有 3 名受试者接受了 MSC 和胰岛联合移植。由于赠款的试点性质，我们的数据显示 BM-MSC 和胰岛联合移植基于这一独特的临床，这是一种安全且有前途的改善移植后胰岛移植的策略。试验经验和动物研究，本研究的目的是进一步评估其安全性和有效性我们的假设是，在更大的 TP-IAT 患者群体中进行自体 MSC 和胰岛联合移植。自体BM-MSCs移植胰岛可以增强移植后胰岛的存活率和功能，使更多的 CP 患者在 TP-IAT 后摆脱糖尿病。 MSCs 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 细胞死亡的指标以及 MSC 治疗的潜在反应/功效。研究不仅迫切需要预防脑瘫患者术后糖尿病，而且可能提供有用的信息来解决患者更复杂的同种异体胰岛细胞移植问题患有 1 型糖尿病。