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Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells
journal contributionposted on 2012-07-24, 00:00 authored by Yong Zhao, Zhaoshun Jiang, Tingbao Zhao, Mingliang Ye, Chengjin Hu, Zhaohui Yin, Heng Li, Ye Zhang, Yalin Diao, Yunxiang Li, Yingjian Chen, Xiaoming Sun, Mary Beth Fisk, Randal Skidgel, Mark Holterman, Bellur Prabhakar, Theodore Mazzone
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.
Supported by grants from the Juvenile Diabetes Research Foundation International, the American Diabetes Association, the University of Illinois at Chicago Center for Clinical and Translational Science pilot grant program (funded by NIH Award Number UL1RR029879 from the National Center For Research Resources), and China Jinan 5150 Program for Oversea Scholar.
Publisher Statement© 2012 Zhao et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. DOI: 10.1186/1741-7015-10-3