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Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells

机译:脐血来源的多能干细胞免疫调节后,通过胰岛β细胞再生逆转1型糖尿病

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Background Inability to control autoimmunity is the primary barrier to developing a cure for type 1 diabetes (T1D). Evidence that human cord blood-derived multipotent stem cells (CB-SCs) can control autoimmune responses by altering regulatory T cells (Tregs) and human islet β cell-specific T cell clones offers promise for a new approach to overcome the autoimmunity underlying T1D. Methods We developed a procedure for Stem Cell Educator therapy in which a patient's blood is circulated through a closed-loop system that separates lymphocytes from the whole blood and briefly co-cultures them with adherent CB-SCs before returning them to the patient's circulation. In an open-label, phase1/phase 2 study, patients (n = 15) with T1D received one treatment with the Stem Cell Educator. Median age was 29 years (range: 15 to 41), and median diabetic history was 8 years (range: 1 to 21). Results Stem Cell Educator therapy was well tolerated in all participants with minimal pain from two venipunctures and no adverse events. Stem Cell Educator therapy can markedly improve C-peptide levels, reduce the median glycated hemoglobin A1C (HbA1C) values, and decrease the median daily dose of insulin in patients with some residual β cell function (n = 6) and patients with no residual pancreatic islet β cell function (n = 6). Treatment also produced an increase in basal and glucose-stimulated C-peptide levels through 40 weeks. However, participants in the Control Group (n = 3) did not exhibit significant change at any follow-up. Individuals who received Stem Cell Educator therapy exhibited increased expression of co-stimulating molecules (specifically, CD28 and ICOS), increases in the number of CD4+CD25+Foxp3+ Tregs, and restoration of Th1/Th2/Th3 cytokine balance. Conclusions Stem Cell Educator therapy is safe, and in individuals with moderate or severe T1D, a single treatment produces lasting improvement in metabolic control. Initial results indicate Stem Cell Educator therapy reverses autoimmunity and promotes regeneration of islet β cells. Successful immune modulation by CB-SCs and the resulting clinical improvement in patient status may have important implications for other autoimmune and inflammation-related diseases without the safety and ethical concerns associated with conventional stem cell-based approaches. Trial registration ClinicalTrials.gov number, NCT01350219 .
机译:背景技术无法控制自身免疫是开发1型糖尿病(T1D)的主要障碍。人脐带血多能干细胞(CB-SCs)可以通过改变调节性T细胞(Tregs)和人胰岛β细胞特异性T细胞克隆来控制自身免疫应答的证据,为克服T1D潜在的自身免疫性的新方法提供了希望。方法我们开发了一种干细胞教育器疗法的程序,其中,患者的血液通过闭环系统循环,该系统将淋巴细胞与全血分离,并在将其返回患者循环之前,将其与粘附的CB-SC短暂地共培养。在一项开放标签的1期/ 2期研究中,患有T1D的患者(n = 15)接受了干细胞教育者的一项治疗。中位年龄为29岁(范围:15至41),中位糖尿病史为8年(范围:1至21)。结果干细胞教育者疗法在所有参与者中耐受良好,两次静脉穿刺疼痛最小,无不良事件。干细胞教育者疗法可显着提高C肽水平,降低中值糖化血红蛋白A 1 C(HbA 1 C值,并降低具有某些残余β细胞功能的患者(n = 6)和无残余胰岛β细胞功能的患者(n = 6)的平均每日胰岛素剂量。在40周内,治疗也使基础和葡萄糖刺激的C肽水平增加。但是,对照组(n = 3)的参与者在任何随访中均未表现出明显变化。接受干细胞教育者治疗的个体表现出共刺激分子(特别是CD28和ICOS)表达增加,CD4 + CD25 + Foxp3 + Treg,并恢复Th1 / Th2 / Th3细胞因子平衡。结论干细胞教育者疗法是安全的,在中度或重度T1D患者中,单一疗法可持久改善代谢控制。初步结果表明,干细胞教育者疗法可逆转自身免疫并促进胰岛β细胞的再生。 CB-SC的成功免疫调节以及患者状况的临床改善可能会对其他自身免疫和炎症相关疾病产生重要影响,而与基于干细胞的常规方法无关的安全性和道德问题。试用注册ClinicalTrials.gov编号,NCT01350219。

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