title: Modulation of Autoimmune T-Cell Memory by Stem Cell Educator Therapy: Phase 1/2 Clinical Trial.
abstract: BACKGROUND
  Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet β cells. The complexities of overcoming autoimmunity in T1D have contributed to the challenges the research community faces when devising successful treatments with conventional immune therapies. Overcoming autoimmune T cell memory represents one of the key hurdles.
  
  
  METHODS
  In this open-label, phase 1/phase 2 study, Caucasian T1D patients (N = 15) received two treatments with the Stem Cell Educator (SCE) therapy, an approach that uses human multipotent cord blood-derived multipotent stem cells (CB-SCs). SCE therapy involves a closed-loop system that briefly treats the patient's lymphocytes with CB-SCs in vitro and returns the "educated" lymphocytes (but not the CB-SCs) into the patient's blood circulation. This study is registered with ClinicalTrials.gov, NCT01350219.
  
  
  RESULTS
  Clinical data demonstrated that SCE therapy was well tolerated in all subjects. The percentage of naïve CD4(+) T cells was significantly increased at 26 weeks and maintained through the final follow-up at 56 weeks. The percentage of CD4(+) central memory T cells (TCM) was markedly and constantly increased at 18 weeks. Both CD4(+) effector memory T cells (TEM) and CD8(+) TEM cells were considerably decreased at 18 weeks and 26 weeks respectively. Additional clinical data demonstrated the modulation of C-C chemokine receptor 7 (CCR7) expressions on naïve T, TCM, and TEM cells. Following two treatments with SCE therapy, islet β-cell function was improved and maintained in individuals with residual β-cell function, but not in those without residual β-cell function.
  
  
  CONCLUSIONS
  Current clinical data demonstrated the safety and efficacy of SCE therapy in immune modulation. SCE therapy provides lasting reversal of autoimmune memory that could improve islet β-cell function in Caucasian subjects.
  
  
  BACKGROUND
  Obra Social "La Caixa", Instituto de Salud Carlos III, Red de Investigación Renal, European Union FEDER Funds, Principado de Asturias, FICYT, and Hackensack University Medical Center Foundation.
authors: Endocrinology Section, Department of Medicine, University de Oviedo, Oviedo 33006, Spain; Endocrinology and Nutrition Service, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Elias
authors: E
authors: Delgado
authors: Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Marcos
authors: M
authors: Perez-Basterrechea
authors: Cellular Biology of Renal Diseases Laboratory, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid 28049, Spain.
authors: Beatriz
authors: B
authors: Suarez-Alvarez
authors: Section of Endocrinology, The First Hospital of Hebei Medical University, Shijiazhuang 050031, PR China.
authors: Huimin
authors: H
authors: Zhou
authors: Hematology and Hemotherapy Service, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Eva Martinez
authors: EM
authors: Revuelta
authors: Hematology and Hemotherapy Service, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Jose Maria
authors: JM
authors: Garcia-Gala
authors: Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Silvia
authors: S
authors: Perez
authors: Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Maria
authors: M
authors: Alvarez-Viejo
authors: Endocrinology Section, Department of Medicine, University de Oviedo, Oviedo 33006, Spain; Endocrinology and Nutrition Service, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Edelmiro
authors: E
authors: Menendez
authors: Department of Immunology, Hospital Universitario Central de Asturias, Oviedo 33011, Spain; Fundación Renal "Iñigo Álvarez de Toledo", Madrid 28003, Spain.
authors: Carlos
authors: C
authors: Lopez-Larrea
authors: Department of Hepatobiliary Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, PR China.
authors: Ruifeng
authors: R
authors: Tang
authors: Department of Pathology, The First Hospital of Hebei Medical University, Shijiazhuang, Hebei 050031, PR China.
authors: Zhenlong
authors: Z
authors: Zhu
authors: Department of Research, Hackensack University Medical Center, Hackensack, NJ 07601, USA.
authors: Wei
authors: W
authors: Hu
authors: CORD:USE Cord Blood Bank, Orlando, FL 32810, USA.
authors: Thomas
authors: T
authors: Moss
authors: CORD:USE Cord Blood Bank, Orlando, FL 32810, USA.
authors: Edward
authors: E
authors: Guindi
authors: Unit of Transplants, Cell Therapy and Regenerative Medicine, Hospital Universitario Central de Asturias, Oviedo 33011, Spain.
authors: Jesus
authors: J
authors: Otero
authors: Department of Research, Hackensack University Medical Center, Hackensack, NJ 07601, USA.
authors: Yong
authors: Y
authors: Zhao
mesh_terms: D000328:Adult; D015551:Autoimmunity; D002096:C-Peptide / Q000097:blood; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D005260:Female; D005500:Follow-Up Studies; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D056747:Immunomodulation; D050417:Insulin-Secreting Cells / Q000276:immunology / Q000378:metabolism; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D054400:Receptors, CCR7 / Q000235:genetics / Q000378:metabolism; D033581:Stem Cell Transplantation; D013234:Stem Cells / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D002096:C-Peptide; D054400:Receptors, CCR7
keywords: AIRE, autoimmune regulator; Autoimmunity; CB-SCs, human cord blood-derived multipotent stem cells; CCR7, C–C chemokine receptor 7; Cord blood stem cell; HLA, human leukocyte antigen; HbA1C, glycated hemoglobin; IL, interleukin; Immune modulation; M2, muscarinic acetylcholine receptor 2; MLR, mixed leukocyte reactions; MNC, mononuclear cells; Memory T cells; OGTT, oral glucose tolerance test; PBMC, peripheral blood mononuclear cells; R, responder; S, stimulator; SCE, Stem Cell Educator; T1D, type 1 diabetes; TCM, central memory T cells; TCR, T-cell receptor; TEM, effector memory T cells; TGF-β1, transforming growth factor-β1; Th, helper T cell; Tregs, regulatory T cells; Type 1 diabetes