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BMC Med. 2012; 10: 3.
Published online Jan 10, 2012. doi:  10.1186/1741-7015-10-3
PMCID: PMC3322343
Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells
Yong Zhao,corresponding author1 Zhaoshun Jiang,2 Tingbao Zhao,3 Mingliang Ye,4 Chengjin Hu,5 Zhaohui Yin,2 Heng Li,6 Ye Zhang,7 Yalin Diao,4 Yunxiang Li,4 Yingjian Chen,5 Xiaoming Sun,5 Mary Beth Fisk,8 Randal Skidgel,9 Mark Holterman,10 Bellur Prabhakar,11 and Theodore Mazzone1
1Section of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 West Polk Street, Chicago, IL 60612 USA
2Section of Endocrinology, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China
3Stem Cell Treatment Center, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China
4Section of Blood Transfusion, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China
5Section of Molecular Diagnostics, General Hospital of Jinan Military Command, 25 Shifan Road, Jinan, Shandong 250031, P.R. China
6Section of Neuronology, Jinan Central Hospital, 105 Jiefang Road, Jinan, Shandong 250020, P.R. China
7Jinan Tianhe Stem Cell Biotechology Co. Ltd., 750 Shunhua Road, Jinan, Shandong 250055, P.R. China
8Texas Cord Blood Bank, 6211 IH-10 West, San Antonio, TX 78201 USA
9Department of Pharmacology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612 USA
10Department of Surgery, University of Illinois at Chicago, 420 NE GLen Oak, Suite 201, Peoria, IL 61603 USA
11Department of Immunology and Microbiology, University of Illinois at Chicago, 835 South Wolcott Avenue, Chicago, IL 60612 USA
corresponding authorCorresponding author.
Yong Zhao: yongzhao/at/uic.edu; Zhaoshun Jiang: zhaoshunjiang/at/yahoo.cn; Tingbao Zhao: tingbaozhao/at/yahoo.cn; Mingliang Ye: mingliangy/at/yahoo.cn; Chengjin Hu: chengjinhu/at/yahoo.cn; Zhaohui Yin: yinzhaohui/at/yahoo.cn; Heng Li: chinaliheng/at/yahoo.com.cn; Ye Zhang: tianhefly2010/at/yahoo.cn; Yalin Diao: ydiao/at/yahoo.cn; Yunxiang Li: yunxiangl/at/yahoo.cn; Yingjian Chen: yinjianchen/at/yahoo.cn; Xiaoming Sun: xsun/at/yahoo.cn; Mary Beth Fisk: sat/at/uic.edu; Randal Skidgel: rskidgel/at/uic.edu; Mark Holterman: rmasjet/at/uic.edu; Bellur Prabhakar: bprabhak/at/uic.edu; Theodore Mazzone: tmazzone/at/uic.edu
Received September 22, 2011; Accepted January 10, 2012.
Abstract
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.
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