title: Immunoprotection and Functional Improvement of Allogeneic Islets in Diabetic Mice, Using a Stable Indoleamine 2,3-Dioxygenase Producing Scaffold.
abstract: BACKGROUND
  We have previously shown that an immunomodulatory enzyme, indoleamine 2,3-dioxygenase (IDO) in dermal fibroblasts generates a tryptophan-deficient environment that selectively inhibits proliferation and induces apoptosis of bystander CD4+ and CD8+ T cells, but not pancreatic islets. Because these immune cells are involved in islet allograft rejection, we hypothesized that transplantation of islets embedded in a novel 3-dimensional composite scaffold within which stable IDO-expressing fibroblasts serve as source of local immunosuppression would lead to normoglycemia in a streptozotocin-induced diabetic mouse model.
  
  
  METHODS
  Islet grafts were prepared by embedding stable IDO-expressing fibroblasts and allogeneic islets into a protease-resistant composite scaffold. Islets function and survival were evaluated in vitro using immunohistochemistry. Allografts were transplanted under the kidney capsule of streptozotocin-induced diabetic mice; viability, function, and criteria for graft take were evaluated. Flow cytometry was performed to determine specific intragraft, draining lymph nodes and spleen T-cell population, and splenocytes alloantigen responsiveness of graft recipients.
  
  
  RESULTS
  The results of a series of in vitro experiments revealed that IDO-expressing fibroblasts do not compromise islet function or survival. The expression of IDO suppressed the proliferation of alloantigen-stimulated splenocytes. The in vivo experiments revealed that local IDO expression delivered by lentiviral vector prolonged islet allograft survival (51.0 ± 2.9 days) by increasing the population of FOXP3+ regulatory T cells at the graft site and graft-draining lymph nodes and preventing T-cell infiltration.
  
  
  CONCLUSIONS
  This study shows that incorporation of islets within our novel matrix that is equipped with stable IDO-expressing fibroblasts prolongs allograft survival.
authors.affiliation: Department of Surgery, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Azadeh
authors.initials: A
authors.lastname: Hosseini-Tabatabaei
authors.forename: Reza Baradar
authors.initials: RB
authors.lastname: Jalili
authors.forename: Mohsen
authors.initials: M
authors.lastname: Khosravi-Maharlooei
authors.forename: Ryan
authors.initials: R
authors.lastname: Hartwell
authors.forename: Ruhangiz T
authors.initials: RT
authors.lastname: Kilani
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhang
authors.forename: Aziz
authors.initials: A
authors.lastname: Ghahary
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D018920:Coculture Techniques; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D005347:Fibroblasts / Q000201:enzymology / Q000276:immunology / Q000637:transplantation*; D015316:Genetic Therapy / Q000379:methods*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis* / Q000235:genetics; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology / Q000601:surgery*; D016381:Islets of Langerhans Transplantation / Q000379:methods*; D008198:Lymph Nodes / Q000201:enzymology / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D013154:Spleen / Q000201:enzymology / Q000276:immunology; D013601:T-Lymphocytes / Q000201:enzymology / Q000276:immunology; D013997:Time Factors; D046509:Tissue Culture Techniques; D054457:Tissue Scaffolds; D014162:Transfection
chemical_list: D015415:Biomarkers; D001786:Blood Glucose; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase