title: IDO-Expressing Fibroblasts Protect Islet Beta Cells From Immunological Attack and Reverse Hyperglycemia in Non-Obese Diabetic Mice.
abstract: Indoleamine 2,3-dioxygenase (IDO) induces immunological tolerance in physiological and pathological conditions. Therefore, we used dermal fibroblasts with stable IDO expression as a cell therapy to: (i) Investigate the factors determining the efficacy of this cell therapy for autoimmune diabetes in non-obese diabetic (NOD) mice; (ii) Scrutinize the potential immunological mechanisms. Newly diabetic NOD mice were randomly injected with either 10 × 10(6) (10M) or 15 × 10(6) (15M) IDO-expressing dermal fibroblasts. Blood glucose levels (BGLs), body weight, plasma kynurenine levels, insulitis severity, islet beta cell function, autoreactive CD8(+) T cells, Th17 cells and regulatory T cells (Tregs) were then investigated in these mice. IL-1β and cleaved caspase-3 levels were assessed in islets co-cultured with IDO-expressing fibroblasts. BGLs in 83% mice treated with 15M IDO-expressing fibroblasts recovered to normal up to 120 days. However, only 17% mice treated with 10M IDO-expressing cells were reversed to normoglycemia. A 15M IDO-expressing fibroblasts significantly reduced infiltrated immune cells in islets and recovered the functionality of remaining islet beta cells in NOD mice. Additionally, they successfully inhibited autoreactive CD8(+) T cells and Th17 cells as well as increased Tregs in different organs of NOD mice. Islet beta cells co-cultured with IDO-expressing fibroblasts had reduced IL-1β levels and cell apoptosis. Both cell number and IDO enzymatic activity contributes to the efficiency of IDO cell therapy. Optimized IDO-expressing fibroblasts successfully reverse the progression of diabetes in NOD mice through induction of Tregs as well as inhibition of beta cell specific autoreactive CD8(+) T cells and Th17 cells. J. Cell. Physiol. 231: 1964-1973, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Reza B
authors.initials: RB
authors.lastname: Jalili
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ruhangiz T
authors.initials: RT
authors.lastname: Kilani
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Sanam Salimi
authors.initials: SS
authors.lastname: Elizei
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ali
authors.initials: A
authors.lastname: Farrokhi
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khosravi-Maharlooei
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Garth L
authors.initials: GL
authors.lastname: Warnock
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ziliang
authors.initials: Z
authors.lastname: Ao
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Lucy
authors.initials: L
authors.lastname: Marzban
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000201:enzymology*; D006943:Hyperglycemia / Q000276:immunology / Q000378:metabolism*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000201:enzymology / Q000276:immunology*; D008297:Male; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D050378:T-Lymphocytes, Regulatory / Q000276:immunology
chemical_list: D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase