Immunoprotection and Functional Improvement of Allogeneic Islets in Diabetic Mice, Using a Stable Indoleamine 2,3-Dioxygenase Producing Scaffold

Transplantation. 2015 Jul;99(7):1341-8. doi: 10.1097/TP.0000000000000661.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers / blood
  • Blood Glucose / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Coculture Techniques
  • Diabetes Mellitus, Experimental / blood
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / genetics
  • Diabetes Mellitus, Experimental / immunology
  • Diabetes Mellitus, Experimental / therapy*
  • Fibroblasts / enzymology
  • Fibroblasts / immunology
  • Fibroblasts / transplantation*
  • Genetic Therapy / methods*
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Survival
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / biosynthesis*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / immunology
  • Islets of Langerhans / surgery*
  • Islets of Langerhans Transplantation / methods*
  • Lymph Nodes / enzymology
  • Lymph Nodes / immunology
  • Lymphocyte Activation
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Spleen / enzymology
  • Spleen / immunology
  • T-Lymphocytes / enzymology
  • T-Lymphocytes / immunology
  • Time Factors
  • Tissue Culture Techniques
  • Tissue Scaffolds*
  • Transfection


  • Biomarkers
  • Blood Glucose
  • Indoleamine-Pyrrole 2,3,-Dioxygenase