Local expression of indoleamine 2,3 dioxygenase in syngeneic fibroblasts significantly prolongs survival of an engineered three-dimensional islet allograft.
OBJECTIVE
The requirement of systemic immunosuppression after islet transplantation is of significant concern and a major drawback to clinical islet transplantation. Here, we introduce a novel composite three-dimensional islet graft equipped with a local immunosuppressive system that prevents islet allograft rejection without systemic antirejection agents. In this composite graft, expression of indoleamine 2,3 dioxygenase (IDO), a tryptophan-degrading enzyme, in syngeneic fibroblasts provides a low-tryptophan microenvironment within which T-cells cannot proliferate and infiltrate islets.


METHODS
Composite three-dimensional islet grafts were engineered by embedding allogeneic mouse islets and adenoviral-transduced IDO-expressing syngeneic fibroblasts within collagen gel matrix. These grafts were then transplanted into renal subcapsular space of streptozotocin diabetic immunocompetent mice. The viability, function, and criteria for graft take were then determined in the graft recipient mice.


RESULTS
IDO-expressing grafts survived significantly longer than controls (41.2 +/- 1.64 vs. 12.9 +/- 0.73 days; P < 0.001) without administration of systemic immunesuppressive agents. Local expression of IDO suppressed effector T-cells at the graft site, induced a Th2 immune response shift, generated an anti-inflammatory cytokine profile, delayed alloantibody production, and increased number of regulatory T-cells in draining lymph nodes, which resulted in antigen-specific impairment of T-cell priming.


CONCLUSIONS
Local IDO expression prevents cellular and humoral alloimmune responses against islets and significantly prolongs islet allograft survival without systemic antirejection treatments. This promising finding proves the potent local immunosuppressive activity of IDO in islet allografts and sets the stage for development of a long-lasting nonrejectable islet allograft using stable IDO induction in bystander fibroblasts.
Jalili
Reza B
RB
Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada.
Forouzandeh
Farshad
F
Rezakhanlou
Alireza Moeen
AM
Hartwell
Ryan
R
Medina
Abelardo
A
Warnock
Garth L
GL
Larijani
Bagher
B
Ghahary
Aziz
A
D000818:Animals; D002470:Cell Survival / Q000502:physiology*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000601:surgery; D015971:Gene Expression Regulation, Enzymologic; D005818:Genetic Engineering / Q000379:methods; D005822:Genetic Vectors; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics*; D007249:Inflammation / Q000235:genetics / Q000517:prevention & control; D016381:Islets of Langerhans Transplantation / Q000276:immunology / Q000502:physiology*; D007518:Isoantibodies / Q000097:blood; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D014184:Transplantation, Homologous / Q000379:methods / Q000502:physiology*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007518:Isoantibodies; D012313:RNA