PD-L1-driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice

Rongying Li, Jeongkyung Lee, Mi Sun Kim, Victoria Liu, Mousumi Moulik, Haiyan Li, Qing Yi, Aini Xie, Wenhao Chen, Lina Yang, Yimin Li, Tsung Huang Tsai, Kazuhiro Oka, Lawrence Chan, Vijay Yechoor

Research output: Contribution to journalArticle

10 Scopus citations

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+

Original languageEnglish (US)
Pages (from-to)529-540
Number of pages12
JournalDiabetes
Volume64
Issue number2
DOIs
StatePublished - Feb 1 2015

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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