Suppression of islet allogeneic immune response by indoleamine 2,3 dioxygenase-expressing fibroblasts.
Success of transplantation of pancreatic islets which is a promising way for restoring efficient insulin regulation in type 1 diabetes depends on lifelong use of immunosuppressive drugs. To eliminate the use of systemic immunosuppressive drugs for islet transplantation, we examined the potential use of a local immunosuppressive factor, indoleamine 2,3-dioxygenase (IDO). Thus, the aim of this study was to determine whether local expression of IDO in bystander syngeneic fibroblasts could prevent islet allogeneic immune response in vitro. C57BL/6 (B6) mouse fibroblasts were induced to express IDO by either IFN-gamma treatment or transduction with an adenoviral vector and were co-cultured with B6 mouse lymphocytes and BALB/c mouse pancreatic islets in the presence or absence of an IDO inhibitor. Proliferation of lymphocytes were then assessed using [(3)H]-thymidine incorporation assay. IDO-expression by co-cultured syngeneic fibroblasts resulted in a five-fold decrease in lymphocyte proliferation rate upon stimulation of lymphocytes by allogeneic mouse pancreatic islets (21.9% +/- 5.3 and 22.1% +/- 4.9 in the preparations with IFN-gamma treated and genetically modified IDO-expressing fibroblasts, respectively vs. 100% in control groups, P < 0.01). Allogeneic response was restored when IDO inhibitor was added to the culture indicating that suppression was due to IDO. In conclusion, this study shows that local expression of IDO by syngeneic bystander fibroblasts can suppress in vitro proliferation of lymphocytes in response to stimulation with allogeneic pancreatic islets. This local immunosuppressive function of IDO may be employed for development of a novel alternative strategy for preventing allogeneic islet graft rejection.
Jalili
Reza B
RB
Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada V6H 3Z6.
Rayat
Gina R
GR
Rajotte
Ray V
RV
Ghahary
Aziz
A
D000818:Animals; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D007371:Interferon-gamma / Q000494:pharmacology; D007515:Islets of Langerhans / Q000201:enzymology* / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology; D007519:Isoantigens; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007519:Isoantigens; D012333:RNA, Messenger; D011994:Recombinant Proteins; D049452:Green Fluorescent Proteins; D007371:Interferon-gamma