title: Reversal of type 1 diabetes via islet β cell regeneration following immune modulation by cord blood-derived multipotent stem cells.
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.
  
  
  BACKGROUND
  ClinicalTrials.gov number, NCT01350219.
authors.affiliation: Section of Endocrinology, Diabetes & Metabolism, Department of Medicine, University of Illinois at Chicago, 1819 West Polk Street, Chicago, IL 60612, USA. yongzhao@uic.edu
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Zhaoshun
authors.initials: Z
authors.lastname: Jiang
authors.forename: Tingbao
authors.initials: T
authors.lastname: Zhao
authors.forename: Mingliang
authors.initials: M
authors.lastname: Ye
authors.forename: Chengjin
authors.initials: C
authors.lastname: Hu
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Yin
authors.forename: Heng
authors.initials: H
authors.lastname: Li
authors.forename: Ye
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yalin
authors.initials: Y
authors.lastname: Diao
authors.forename: Yunxiang
authors.initials: Y
authors.lastname: Li
authors.forename: Yingjian
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Sun
authors.forename: Mary Beth
authors.initials: MB
authors.lastname: Fisk
authors.forename: Randal
authors.initials: R
authors.lastname: Skidgel
authors.forename: Mark
authors.initials: M
authors.lastname: Holterman
authors.forename: Bellur
authors.initials: B
authors.lastname: Prabhakar
authors.forename: Theodore
authors.initials: T
authors.lastname: Mazzone
mesh_terms: D000293:Adolescent; D000328:Adult; D002096:C-Peptide / Q000097:blood; D002450:Cell Communication; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000628:therapy*; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D005500:Follow-Up Studies; D006801:Humans; D056747:Immunomodulation; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000502:physiology*; D008297:Male; D039902:Multipotent Stem Cells / Q000276:immunology* / Q000637:transplantation*; D020127:Recovery of Function; D012038:Regeneration; D016176:T-Lymphocyte Subsets / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D002096:C-Peptide