title: Immunogenicity of human embryonic stem cell-derived beta cells.
abstract: To overcome the donor shortage in the treatment of advanced type 1 diabetes by islet transplantation, human embryonic stem cells (hESCs) show great potential as an unlimited alternative source of beta cells. hESCs may have immune privileged properties and it is important to determine whether these properties are preserved in hESC-derived cells.
  
  
  
  We comprehensively investigated interactions of both innate and adaptive auto- and allo-immunity with hESC-derived pancreatic progenitor cells and hESC-derived endocrine cells, retrieved after in-vivo differentiation in capsules in the subcutis of mice.
  
  
  
  We found that hESC-derived pancreatic endodermal cells expressed relatively low levels of HLA endorsing protection from specific immune responses. HLA was upregulated when exposed to IFNγ, making these endocrine progenitor cells vulnerable to cytotoxic T cells and alloreactive antibodies. In vivo-differentiated endocrine cells were protected from complement, but expressed more HLA and were targets for alloreactive antibody-dependent cellular cytotoxicity and alloreactive cytotoxic T cells. After HLA compatibility was provided by transduction with HLA-A2, preproinsulin-specific T cells killed insulin-producing cells.
  
  
  
  hESC-derived pancreatic progenitors are hypoimmunogenic, while in vivo-differentiated endocrine cells represent mature targets for adaptive immune responses. Our data support the need for immune intervention in transplantation of hESC-derived pancreatic progenitors. Cell-impermeable macro-encapsulation may suffice.
authors: Department of Immunohaematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, NL-2300 RC, Leiden, the Netherlands.|JDRF Center for Beta Cell Therapy in Diabetes.
authors: Cornelis R
authors: CR
authors: van der Torren
authors: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, the Netherlands.
authors: Arnaud
authors: A
authors: Zaldumbide
authors: Department of Immunohaematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, NL-2300 RC, Leiden, the Netherlands.|JDRF Center for Beta Cell Therapy in Diabetes.
authors: Gaby
authors: G
authors: Duinkerken
authors: Department of Immunohaematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, NL-2300 RC, Leiden, the Netherlands.
authors: Simone H
authors: SH
authors: Brand-Schaaf
authors: Department of Immunobiology, King's College London School of Medicine, London, UK.
authors: Mark
authors: M
authors: Peakman
authors: JDRF Center for Beta Cell Therapy in Diabetes.|Diabetes Research Center, Brussels Free University-VUB, Brussels, Belgium.
authors: Geert
authors: G
authors: Stangé
authors: ViaCyte, Inc., San Diego, CA, USA.
authors: Laura
authors: L
authors: Martinson
authors: ViaCyte, Inc., San Diego, CA, USA.
authors: Evert
authors: E
authors: Kroon
authors: ViaCyte, Inc., San Diego, CA, USA.
authors: Eugene P
authors: EP
authors: Brandon
authors: JDRF Center for Beta Cell Therapy in Diabetes.|Diabetes Research Center, Brussels Free University-VUB, Brussels, Belgium.
authors: Daniel
authors: D
authors: Pipeleers
authors: Department of Immunohaematology and Blood Transfusion, E3-Q, Leiden University Medical Center, P.O. Box 9600, NL-2300 RC, Leiden, the Netherlands. boroep@lumc.nl.|JDRF Center for Beta Cell Therapy in Diabetes, . boroep@lumc.nl.|Department of Diabetes Immunology, Diabetes and Metabolism Research Institute at the Beckman Research Institute, City of Hope, Duarte, CA, USA. boroep@lumc.nl.
authors: Bart O
authors: BO
authors: Roep
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D064591:Allografts; D015551:Autoimmunity; D002478:Cells, Cultured; D015789:HLA-A2 Antigen; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D056724:Immunity, Humoral / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*
chemical_list: D015789:HLA-A2 Antigen; D007371:Interferon-gamma
keywords: Allograft rejection; Autoimmunity; Beta cells; Embryonic stem cells; Transplantation