title: Tolerance induction and reversal of diabetes in mice transplanted with human embryonic stem cell-derived pancreatic endoderm.
abstract: Type 1 diabetes (T1D) is an autoimmune disease caused by T cell-mediated destruction of insulin-producing β cells in the islets of Langerhans. In most cases, reversal of disease would require strategies combining islet cell replacement with immunotherapy that are currently available only for the most severely affected patients. Here, we demonstrate that immunotherapies that target T cell costimulatory pathways block the rejection of xenogeneic human embryonic-stem-cell-derived pancreatic endoderm (hESC-PE) in mice. The therapy allowed for long-term development of hESC-PE into islet-like structures capable of producing human insulin and maintaining normoglycemia. Moreover, short-term costimulation blockade led to robust immune tolerance that could be transferred independently of regulatory T cells. Importantly, costimulation blockade prevented the rejection of allogeneic hESC-PE by human PBMCs in a humanized model in vivo. These results support the clinical development of hESC-derived therapy, combined with tolerogenic treatments, as a sustainable alternative strategy for patients with T1D.
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Szot
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Mahesh
authors.initials: M
authors.lastname: Yadav
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jiena
authors.initials: J
authors.lastname: Lang
authors.affiliation: ViaCyte, Incorporated, San Diego, CA 92121, USA.
authors.forename: Evert
authors.initials: E
authors.lastname: Kroon
authors.affiliation: ViaCyte, Incorporated, San Diego, CA 92121, USA.
authors.forename: Justin
authors.initials: J
authors.lastname: Kerr
authors.affiliation: ViaCyte, Incorporated, San Diego, CA 92121, USA.
authors.forename: Kuniko
authors.initials: K
authors.lastname: Kadoya
authors.affiliation: ViaCyte, Incorporated, San Diego, CA 92121, USA.
authors.forename: Eugene P
authors.initials: EP
authors.lastname: Brandon
authors.affiliation: ViaCyte, Incorporated, San Diego, CA 92121, USA.
authors.forename: Emmanuel E
authors.initials: EE
authors.lastname: Baetge
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA.
authors.forename: Hélène
authors.initials: H
authors.lastname: Bour-Jordan
authors.affiliation: Diabetes Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: jeff.bluestone@ucsf.edu.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Bluestone
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000473:pathology / Q000628:therapy*; D004707:Endoderm / Q000166:cytology* / Q000276:immunology*; D000066449:Human Embryonic Stem Cells / Q000637:transplantation*; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D010179:Pancreas / Q000166:cytology* / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014183:Transplantation, Heterologous