title: PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice.
abstract: A breakdown in self-tolerance underlies autoimmune destruction of β-cells and type 1 diabetes. A cure by restoring β-cell mass is limited by the availability of transplantable β-cells and the need for chronic immunosuppression. Evidence indicates that inhibiting costimulation through the PD-1/PD-L1 pathway is central to immune tolerance. We therefore tested whether induction of islet neogenesis in the liver, protected by PD-L1-driven tolerance, reverses diabetes in NOD mice. We demonstrated a robust induction of neo-islets in the liver of diabetic NOD mice by gene transfer of Neurogenin3, the islet-defining factor, along with betacellulin, an islet growth factor. These neo-islets expressed all the major pancreatic hormones and transcription factors. However, an enduring restoration of glucose-stimulated insulin secretion and euglycemia occurs only when tolerance is also induced by the targeted overexpression of PD-L1 in the neo-islets, which results in inhibition of proliferation and increased apoptosis of infiltrating CD4(+) T cells. Further analysis revealed an inhibition of cytokine production from lymphocytes isolated from the liver but not from the spleen of treated mice, indicating that treatment did not result in generalized immunosuppression. This treatment strategy leads to persistence of functional neo-islets that resist autoimmune destruction and consequently an enduring reversal of diabetes in NOD mice.
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Rongying
authors.initials: R
authors.lastname: Li
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Jeongkyung
authors.initials: J
authors.lastname: Lee
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Mi-sun
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Victoria
authors.initials: V
authors.lastname: Liu
authors.affiliation: Division of Cardiology, Department of Pediatrics, University of Texas Medical School at Houston, Houston, TX.
authors.forename: Mousumi
authors.initials: M
authors.lastname: Moulik
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Cancer Biology, Cleveland Clinic, Lerner Research Institute, Cleveland, OH.
authors.forename: Qing
authors.initials: Q
authors.lastname: Yi
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Aini
authors.initials: A
authors.lastname: Xie
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Wenhao
authors.initials: W
authors.lastname: Chen
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Lina
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Yimin
authors.initials: Y
authors.lastname: Li
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX.
authors.forename: Tsung Huang
authors.initials: TH
authors.lastname: Tsai
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX Division of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Oka
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX Division of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX vyechoor@bcm.edu lchan@bcm.edu.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Chan
authors.affiliation: Division of Diabetes, Endocrinology and Metabolism, Diabetes and Endocrinology Research Center, and Department of Medicine, Baylor College of Medicine, Houston, TX Division of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX vyechoor@bcm.edu lchan@bcm.edu.
authors.forename: Vijay
authors.initials: V
authors.lastname: Yechoor
mesh_terms: D000818:Animals; D017209:Apoptosis; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007165:Immunosuppression Therapy; D007515:Islets of Langerhans / Q000166:cytology / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology
chemical_list: D060890:B7-H1 Antigen; D051792:Basic Helix-Loop-Helix Proteins; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins; C498919:Cd274 protein, mouse; C498833:Foxp3 protein, mouse; C407737:Neurog3 protein, mouse