Cellular Therapy for Type 1 Diabetes using Mesenchymal Stem Cells

使用间充质干细胞进行 1 型糖尿病的细胞疗法

• 批准号: 10376342
• 负责人: Hongjun Wang
• 金额: $ 62.8万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10376342
• 关键词: Adult; Aftercare; Age; Allogenic; Area Under Curve; Attenuated; Autoimmune; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Autologous; Beta Cell; Biological Markers; Bone Marrow; C-Peptide; CD80 gene; CD86 gene; Cell Count; Cell Death; Cell Therapy; Cell physiology; Cells; Clinical Data; Clinical Treatment; Clinical Trials; DNA; Data; Diabetes Mellitus; Disease; Dose; Double-Blind Method; Enrollment; Fatty acid glycerol esters; Funding; Goals; Grant; Harvest; Hyperglycemia; Immune; Immune response; Immune system; Immunosuppression; Immunotherapy; Inbred NOD Mice; Inflammatory; Infrastructure; Infusion procedures; Insulin; Insulin-Dependent Diabetes Mellitus; Interdisciplinary Study; Interleukin-2; Intervention; Lupus; MHC Class II Genes; Measures; Mesenchymal; Mesenchymal Stem Cells; Metabolic; Morbidity - disease rate; Natural regeneration; Newly Diagnosed; Pancreas; Pancreatic Injury; Patient Recruitments; Patients; Peripheral Blood Mononuclear Cell; Placebo Control; Placebos; Plastic Surgical Procedures; Procedures; Property; Randomized; Regulatory T-Lymphocyte; Reperfusion Injury; Reporting; Running; Safety; Serious Adverse Event; Serum; Signal Transduction; Source; Structure of beta Cell of islet; Sweden; Testing; Th2 Cells; Therapeutic; Time; Tissues; Transforming Growth Factor beta Receptors; Umbilical cord structure; United States; Wound healing therapy; adult stem cell; autoreactive B cell; base; clinical center; cytokine; experience; immune system function; immunoregulation; improved; insulin dependent diabetes mellitus onset; insulin secretion; islet; mRNA Expression; mouse model; participant enrollment; pre-clinical; preconditioning; preservation; receptor; regeneration potential; regenerative; response; safety and feasibility; standard of care; stem cell therapy; stem cells

: Two major hurdles must be overcome to cure type 1 diabetes (T1D): (i) the autoimmune response and (ii) destruction of insulin-secreting islets/β cells. Immunotherapies, including improved immune regulation using ex vivo expanded regulatory T-cell (Tregs) or low-dose interleukin-2 (IL-2), may be able to suppress autoimmunity. However, immunomodulation is not expected to directly stimulate regeneration of β cells. On the other hand, mesenchymal stromal/stem cells (MSCs) possess both immunomodulatory and regenerative properties and represent a promising new intervention for autoimmune diseases. MSCs are an accepted therapeutic for wound healing in plastic surgery applications and are being tested in clinical trials for the treatment of autoimmune and inflammatory diseases, ischemia reperfusion injuries, diabetes and other diseases. Our group and others found that after infusion into spontaneous non-obese diabetic (NOD) mice, MSCs migrated into the injured pancreas, reduced hyperglycemia and attenuated Th1 immune responses concomitant with the expansion/proliferation of Tregs. Most importantly, MSC infusion led to increased mRNA expression of IL-2 and TGF-β receptors in pancreatic Treg cells in NOD mice. A pilot clinical trial in Sweden showed that a single infusion of autologous bone marrow-derived MSCs preserved insulin secretion in adult patients with new-onset T1D. This study has yet to be systemically tested in patients in the United States and no mechanistic studies have been reported that explain the benefit observed. MSCs derived from umbilical cord (UC-MSCs) show greater cell yield, a less invasive harvesting procedure with associated reduced morbidity, and stronger immunosuppressive and regenerative potential and are a popular source for cell therapy. Based on the above principles and the successful patient enrollment in our one-year R01 grant, we propose a renewal of a randomized, double-blind, placebo- controlled, single-center clinical trial to determine the efficacy of UC-MSC therapy in patients with new-onset T1D. Our working hypothesis is that systemic administration of MSCs freshly expanded ex vivo reduces progression of diabetes and preserves insulin secretion through restoring normal function of the immune system and preservation/improvement of pancreatic β cells in patients with T1D. We will test this hypothesis by the following aims: (i). Determine the safety and efficacy of MSC therapy in patients with new-onset T1D when added to standard-of-care, and (ii) Define the mechanisms of protection and elucidate biomarker(s) of efficacy of MSC therapy in T1D patients. The early safety of MSC therapy is documented in our first 7 adult patients age 18-30 enrolled over 7 months and from multiple MSC Trials for various diseases. MSCs may constitute an important therapeutic advancement for T1D.

: 治疗1型糖尿病（T1 D）必须克服两个主要障碍：（i）自身免疫反应和（ii）胰岛素分泌胰岛/β细胞的破坏。免疫疗法，包括使用离体扩增的调节性T细胞（TCFs）或低剂量白细胞介素-2（IL-2）改善免疫调节，可能能够抑制自身免疫。然而，预期免疫调节不会直接刺激β细胞的再生。另一方面，间充质基质/干细胞（MSC）具有免疫调节和再生特性，代表了一种有前途的新的干预自身免疫性疾病。MSC是整形外科应用中伤口愈合的公认治疗剂，并且正在临床试验中测试用于治疗自身免疫性和炎症性疾病、缺血再灌注损伤、糖尿病和其他疾病。我们的小组和其他人发现，在输注到自发性非肥胖糖尿病（NOD）小鼠后，MSC迁移到受损的胰腺，降低高血糖症和减弱Th 1免疫反应伴随着Tcl 3的扩增/增殖。最重要的是，MSC输注导致NOD小鼠中胰腺Treg细胞中IL-2和TGF-β受体的mRNA表达增加。瑞典的一项初步临床试验表明，单次输注自体骨髓来源的MSC可以保护新发T1 D成人患者的胰岛素分泌。这项研究尚未在美国患者中进行系统性测试，也没有机制研究报告可以解释观察到的获益。来源于脐带的间充质干细胞（UC-MSC）显示出更高的细胞产量，具有降低发病率的侵入性较小的收获程序，以及更强的免疫抑制和再生潜力，并且是细胞治疗的流行来源。基于上述原则和我们的一年R 01基金中成功招募的患者，我们建议更新一项随机、双盲、安慰剂对照、单中心临床试验，以确定UC-MSC治疗新发T1 D患者的疗效。我们的工作假设是，全身施用离体新鲜扩增的MSC通过恢复T1 D患者的免疫系统的正常功能和胰腺β细胞的保存/改善来减少糖尿病的进展并保存胰岛素分泌。我们将通过以下目的来检验这一假设：（1）。确定MSC治疗在新发T1 D患者中加入标准治疗时的安全性和有效性，以及（ii）定义保护机制并阐明MSC治疗在T1 D患者中有效性的生物标志物。MSC治疗的早期安全性在我们的前7名18-30岁的成年患者中记录，这些患者在7个月内入组，并来自多种疾病的多个MSC试验。MSC可能构成T1 D的重要治疗进展。