title: Mouse pancreatic islets are resistant to indoleamine 2,3 dioxygenase-induced general control nonderepressible-2 kinase stress pathway and maintain normal viability and function.
abstract: Islet transplantation is a promising treatment for diabetes. However, it faces several challenges including requirement of systemic immunosuppression. Indoleamine 2,3-dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor. Local expression of IDO in bystander fibroblasts suppresses islet allogeneic immune response in vitro. The aim of the present study was to investigate the impact of IDO on viability and function of mouse islets embedded within IDO-expressing fibroblast-populated collagen scaffold. Mouse islets were embedded within collagen matrix populated with IDO adenovector-transduced or control fibroblasts. Proliferation, insulin content, glucose responsiveness, and activation of general control nonderepressible-2 kinase stress-responsive pathway were then measured in IDO-exposed islets. In vivo viabilities of composite islet grafts were also tested in a syngeneic diabetic animal model. No reduction in islet cells proliferation was detected in both IDO-expressing and control composites compared to the baseline rates. Islet functional studies showed normal insulin content and secretion in both preparations. In contrast to lymphocytes, general control nonderepressible-2 kinase pathway was not activated in islets cocultured with IDO-expressing fibroblasts. When transplanted to diabetic mice, syngeneic IDO-expressing composite islet grafts were functional up to 100 days tested. These findings collectively confirm normal viability and functionality of islets cocultured with IDO-expressing cells and indicate the feasibility of development of a functional nonrejectable islet graft.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Reza B
authors.initials: RB
authors.lastname: Jalili
authors.forename: Farshad
authors.initials: F
authors.lastname: Forouzandeh
authors.forename: Alireza
authors.initials: A
authors.lastname: Moeenrezakhanlou
authors.forename: Gina R
authors.initials: GR
authors.lastname: Rayat
authors.forename: Ray V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: Hasan
authors.initials: H
authors.lastname: Uludag
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D000818:Animals; D002470:Cell Survival; D018920:Coculture Techniques; D003094:Collagen; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000502:physiology; D015151:Immunoblotting; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000276:immunology / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023822:Tissue Engineering / Q000379:methods*; D054457:Tissue Scaffolds; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: C497250:Ddit3 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D051742:Transcription Factor CHOP; D003094:Collagen; C070634:Eif2ak4 protein, mouse; D017346:Protein Serine-Threonine Kinases